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Zhao L, Liu P, Sauvat A, Carnet Le Provost K, Liu J, Checcoli A, Pol J, Kepp O, Kroemer G, Bezu L. Dexmedetomidine induces immunogenic cancer cell death and sensitizes tumors to PD-1 blockade. J Immunother Cancer 2025; 13:e010714. [PMID: 40480656 PMCID: PMC12142037 DOI: 10.1136/jitc-2024-010714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 05/14/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Local anesthetics promote anticancer immune responses. A machine learning-based algorithm trained with information on the biological effects and molecular descriptors of analgesics, anesthetics, hypnotics and opioids predicted antitumor effects for dexmedetomidine (DEX). DEX is a sedative acting as an alpha2-adrenoceptor (ADRA2) agonist. Based on these premises, we investigated the putative antineoplastic effects of DEX. RESULTS In vitro, DEX promoted premortem stresses such as autophagy and partial endoplasmic reticulum stress with the phosphorylation of eukaryotic initiation factor 2 alpha and the inhibition of the splicing of X-box binding protein 1. DEX elicited the biomarkers of immunogenic cell death, including the release of ATP and high-mobility group box 1 protein, and the cell surface exposure of calreticulin, enhancing the engulfment of malignant cells by dendritic cells. In immunocompetent mice, DEX decreased the progression of colorectal cancers, fibrosarcomas, mammary carcinomas and melanomas, as it improved overall survival. These effects were inhibited by the ADRA2 antagonist yohimbine, suggesting that DEX mediates its anticancer effects at least in part on-target. Depending on the specific tumor model, DEX also enhanced the cytotoxic T cell/regulatory T cell ratio in the tumor bed and draining lymph nodes. Programmed cell death protein 1 blockade tended to improve DEX effects. After rechallenge with antigenically identical cells, no tumor appeared, indicating the formation of immunological memory. CONCLUSIONS These results confirm the machine learning-predicted anticancer activity of DEX. Beyond its utility as a sedative agent in oncological intensive care, DEX may improve anticancer immunosurveillance and sensitize tumors to immune checkpoint blockade.
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Affiliation(s)
- Liwei Zhao
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Peng Liu
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Allan Sauvat
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Killian Carnet Le Provost
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Jiani Liu
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Andrea Checcoli
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Jonathan Pol
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Oliver Kepp
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Guido Kroemer
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Lucillia Bezu
- INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
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Feng X, Dhandore S, Liu Y, Singh K, Ortu F, Suntharalingam K. Osteosarcoma Cell and Osteosarcoma Stem Cell Potent Immunogenic Bi-Nuclear Gallium(III) Complexes. Chemistry 2025; 31:e202500747. [PMID: 40202773 PMCID: PMC12099189 DOI: 10.1002/chem.202500747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/05/2025] [Accepted: 04/08/2025] [Indexed: 04/10/2025]
Abstract
We report the synthesis, characterization, anti-osteosarcoma and anti-osteosarcoma stem cells (OSC) properties (cytotoxic and immunogenic) of a series of bi-nuclear gallium(III) complexes with tridentate Schiff base ligands and 8-hydroxyquinoline (1-4). According to monolayer cytotoxicity studies, 1-4 display micromolar potency toward bulk osteosarcoma cells and OSCs. The most effective complex in series 2 is up to 13-fold more potent toward OSCs than cisplatin and carboplatin (the only metallodrugs used in the clinic to treat osteosarcoma). Remarkably, the bi-nuclear gallium(III) complexes 1-4 are significantly more potent toward 3D-cultured sarcospheres than OSCs cultured in monolayers indicating effective penetration of the sarcosphere multicellular architecture. The bi-nuclear gallium(III) complexes 1-4 are up to 53-fold more potent toward sarcospheres than cisplatin and carboplatin. Mechanistic studies show that gallium(III) complex 2 kills osteosarcoma cells by caspase-dependent apoptosis and paraptosis, leading to the release of danger-associated molecular patterns associated with immunogenic cell death. Osteosarcoma cells and OSCs treated with gallium(III) complex 2 are effectively phagocytosed by immune cells, highlighting its immunogenic potential. As far as it is known, gallium(III) complex 2 is the first metal complex to evoke an immunogenic response toward both bulk osteosarcoma cells and OSCs.
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Affiliation(s)
- Xiao Feng
- School of ChemistryUniversity of LeicesterLeicesterLE1 7RHUK
| | - Shruti Dhandore
- School of ChemistryUniversity of LeicesterLeicesterLE1 7RHUK
| | - Yu Liu
- School of ChemistryUniversity of LeicesterLeicesterLE1 7RHUK
| | - Kuldip Singh
- School of ChemistryUniversity of LeicesterLeicesterLE1 7RHUK
| | - Fabrizio Ortu
- School of ChemistryUniversity of LeicesterLeicesterLE1 7RHUK
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Perez-Medina M, Benito-Lopez JJ, Aguilar-Cazares D, Lopez-Gonzalez JS. A Comprehensive Review of Long Non-Coding RNAs in the Cancer-Immunity Cycle: Mechanisms and Therapeutic Implications. Int J Mol Sci 2025; 26:4821. [PMID: 40429961 PMCID: PMC12111859 DOI: 10.3390/ijms26104821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 05/10/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of the dynamic interplay between cancer progression and immune responses. This review explored their influence on key processes of the cancer-immunity cycle, such as immune cell differentiation, antigen presentation, and tumor immunogenicity. By modulating tumor escape from the immune response, therapeutic resistance, and tumor-stroma interactions, lncRNAs actively shape the tumor microenvironment. Due to their growing knowledge in the area of immune suppression, directly intervening in the induction of regulatory T cells (Tregs), M2 macrophages, and regulating immune checkpoint pathways such as PD-L1, CTLA-4, and others, lncRNAs can be considered promising therapeutic targets. Advances in single-cell technologies and immunotherapy have significantly expanded our understanding of lncRNA-driven regulatory networks, paving the way for novel precision medicine approaches. Ultimately, we discussed how targeting lncRNAs could enhance cancer immunotherapy, offering new avenues for biomarker discovery and therapeutic intervention.
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Affiliation(s)
- Mario Perez-Medina
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
- Asociación Para Evitar la Ceguera en México, I. A. P., Mexico City 04030, Mexico
| | - Jesus J. Benito-Lopez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
| | - Dolores Aguilar-Cazares
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
| | - Jose S. Lopez-Gonzalez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.P.-M.); (J.J.B.-L.); (D.A.-C.)
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Zou JX, Chang MR, Kuznetsov NA, Kee JX, Babak MV, Ang WH. Metal-based immunogenic cell death inducers for cancer immunotherapy. Chem Sci 2025; 16:6160-6187. [PMID: 40160356 PMCID: PMC11949249 DOI: 10.1039/d4sc08495k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/24/2025] [Indexed: 04/02/2025] Open
Abstract
Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.
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Affiliation(s)
- Jiao Xia Zou
- Department of Chemistry, National University of Singapore 4 Science Drive 2 Singapore 117544 Singapore
| | - Meng Rui Chang
- Department of Chemistry, National University of Singapore 4 Science Drive 2 Singapore 117544 Singapore
| | - Nikita A Kuznetsov
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong 83 Tat Chee Avenue Hong Kong SAR 999077 People's Republic of China
| | - Jia Xuan Kee
- Department of Chemistry, National University of Singapore 4 Science Drive 2 Singapore 117544 Singapore
| | - Maria V Babak
- Drug Discovery Lab, Department of Chemistry, City University of Hong Kong 83 Tat Chee Avenue Hong Kong SAR 999077 People's Republic of China
| | - Wee Han Ang
- Department of Chemistry, National University of Singapore 4 Science Drive 2 Singapore 117544 Singapore
- NUS Graduate School - Integrative Science and Engineering Programme (ISEP), National University of Singapore 21 Lower Kent Ridge Rd Singapore 119077 Singapore
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Huang J, Shi J, Ma N, Li Y, Jin W, Zhang H, Zhang X, Luo N, Ding Y, Xie Q, Li Q, Xiong Y. Celastrol-loaded ginsenoside Rg3 liposomes enhance anti-programmed death ligand 1 immunotherapy by inducing immunogenic cell death in triple-negative breast cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156514. [PMID: 39986227 DOI: 10.1016/j.phymed.2025.156514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 02/05/2025] [Accepted: 02/13/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC), characterized by high heterogeneity and invasiveness. Currently, inducing immunogenic cell death (ICD) of tumor cells through approaches such as radiotherapy and chemotherapy is an effective strategy to enhance the response to anti-programmed death-ligand 1 antibody (aPD-L1) therapy in TNBC. However, radiotherapy and chemotherapy treatments often upregulate PD-L1 expression in tumor cells, thereby weakening the tumor cells' response to aPD-L1. Celastrol exhibits broad-spectrum and potent anti-tumor activity, efficiently inducing ICD without increasing PD-L1 levels in tumor cells. PURPOSE This study aims to elucidate the tumor-targeting effects of celastrol-loaded liposomes and its synergistic efficacy and mechanism of action in combination with aPD-L1 against TNBC. METHODS The Rg3 liposomes loaded with celastrol (Cel-Rg3-Lp) were prepared using the thin-film hydration method. BALB/c mice were utilized to establish an in situ breast cancer model. Mice were intravenously injected with Cel-Rg3-Lp at a dosage of celastrol 1 mg/kg once every two days for a total of 7 injections. Flow cytometry, western blot, and immunofluorescence techniques were employed to investigate the synergistic effects and mechanisms of Cel-Rg3-Lp combined with aPD-L1 in the treatment of TNBC. RESULTS The findings of this study demonstrate that after 7 administrations of Cel-Rg3-Lp (1 mg/kg celastrol, intravenously), significant anti-tumor effects are observed, including the recruitment of CD8+T cells and dendritic cells (DCs), while reducing the infiltration of immunosuppressive cells. The therapeutic efficacy was further enhanced when combined with aPD-L1. Additionally, Cel-Rg3-Lp markedly downregulated glucose-regulated protein 78 (GRP78) expression, thereby inducing ICD in tumor cells. CONCLUSION This study successfully constructed a multifunctional liposome and proposed a mechanism for inducing ICD through the GRP78-endoplasmic reticulum stress pathway. The liposome downregulates GRP78, triggering endoplasmic reticulum stress in tumor cells, inducing ICD, activating DCs, and enhancing antigen presentation to T cells. This improves the tumor immune microenvironment and provides a theoretical foundation for combining Cel-Rg3-Lp with aPD-L1 in the treatment of TNBC. This mechanism opens unique prospects for using celastrol in TNBC therapy and enhancing the effectiveness of immunotherapy.
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Affiliation(s)
- Jingyi Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Jingbin Shi
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ninghui Ma
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yujie Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Wanyu Jin
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Hongyan Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Department of Pharmacy, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China
| | - Xin Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ningchao Luo
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ye Ding
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Qiong Xie
- Gynecology Department, Zhoushan Hospital of Traditional Chinese Medicine (Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University), Zhoushan, Zhejiang 316000, China.
| | - Qiushuang Li
- Center of Clinical Evaluation and Analysis, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310053, China.
| | - Yang Xiong
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
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Tang L, Chang X, Shi J, Wen Z, Bi C, Liu W. More than just DNA damage: Pt(ΙΙ)-NHC complexes derived from 4,5-diarylimidazoles augment immunogenic cell death. Eur J Med Chem 2025; 282:117014. [PMID: 39566241 DOI: 10.1016/j.ejmech.2024.117014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/26/2024] [Accepted: 10/28/2024] [Indexed: 11/22/2024]
Abstract
Platinum-based drugs are a mainstay in chemotherapy, with traditional forms exerting their work directly on DNA. In recent years, it has been observed that platinum complexes had the potential to induce immunogenic cell death (ICD) and effectively trigger antitumor immune responses. Herein, to obtain novel platinum complexes with chemo-immunological properties, a series of Pt(ΙΙ)-N-heterocyclic carbene (Pt(ΙΙ)-NHC) complexes derived from 4,5-diarylimidazoles were synthesized. Among them, the dominant complex 3f was proved to exhibit better anti-liver cancer capacity compared to cisplatin and oxaliplatin. Complex 3f showed the ability to cause DNA damage by binding to DNA. In addition, it triggered intracellular reactive oxygen species (ROS) generation, affected the function of mitochondria, and blocked cells in G0/G1 phase, ultimately induced apoptosis in liver cancer cells. Furthermore, complex 3f activated endoplasmic reticulum stress (ERS) which promoted the release of damage-associated molecular patterns (DAMPs), induced ICD and dendritic cells (DCs) maturation. Interestingly, complex 3f also upregulated PD-L1, consequently converted "cold tumors" into "hot tumors". Overall, complex 3f had the potential to be regarded as a promising chemoimmunotherapy for the treatment of liver cancer.
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Affiliation(s)
- Lu Tang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xingyu Chang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Wuhe Center for Disease Control and Prevention, Bengbu, 233300, China
| | - Jing Shi
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhenfan Wen
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Chunyang Bi
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wukun Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Giuliani J, Tebano U, Mandarà M, Franceschetto A, Giorgi C, Missiroli S, Gabbani M, Napoli G, Luca N, Mangiola D, Muraro M, Perrone M, Pinton P, Fiorica F. "Add More Arrows to Your Quiver": The Role of Adding Another Chemotherapy Drug to Fluoropyrimidine and Long Term Radiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis. J Clin Med 2025; 14:345. [PMID: 39860350 PMCID: PMC11765640 DOI: 10.3390/jcm14020345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/23/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Objectives: Despite optimal local control obtained with neoadjuvant chemoradiotherapy (CRT), data on overall survival (OS) and disease-free survival (DFS) of local advanced rectal cancer patients are still equivocal. This meta-analysis aimed to estimate the pathological complete response (pCR), regression rate, DFS, and OS probabilities of rectal cancer patients treated with a second chemotherapy drug added to fluoropyrimidine and long-term radiotherapy. Methods: Computerized bibliographic searches of MEDLINE, PUBMED, Web of Science and the Cochrane Central Register of Controlled Trials databases (1970-2023) were supplemented with hand searches of reference lists. Studies were included if they were randomised controlled trials (RCTs) comparing intensified chemotherapy with CRT to preoperative CRT and if they had patients with resectable, histologically proven rectal adenocarcinoma without metastases. Results: Eighteen RCTs (7695 patients) were analysed. Data on population, intervention, and outcomes were extracted from each RCT, following the intention-to-treat method, by three independent observers and combined using the DerSimonian and Laird methods. A chemotherapy with two drug and long-term radiotherapy CRT, compared to preoperative CRT (fluoropyrimidine and long-term radiotherapy), significantly increases the rate of pathological complete response (OR 1.37 (95% CI, 1.16-1.63) p = 0.0003) and the regression rate (OR 1.57 (95% CI, 1.16-2.14) p < 0.00001). Furthermore, it increases DFS (HR 0.87 (95% CI, 0.79 to 0.95) p = 0.002 and OS HR 0.84 (95% CI, 0.74 to 0.95) p = 0.007). The risk of severe adverse events (≥G3) is increased OR 1.96 (95% CI 1.35-2.85), p = 0.0005. Conclusions: In patients with resectable rectal cancer, intensified chemotherapy can reduce by 13% the risk of disease progression and by 16% the risk of death.
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Affiliation(s)
- Jacopo Giuliani
- Department of Clinical Oncology, Section of Medical Oncology, AULSS 9 Scaligera, 37045 Legnago, Italy; (J.G.); (M.M.); (D.M.)
| | - Umberto Tebano
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
| | - Marta Mandarà
- Department of Clinical Oncology, Section of Medical Oncology, AULSS 9 Scaligera, 37045 Legnago, Italy; (J.G.); (M.M.); (D.M.)
| | - Antonella Franceschetto
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
| | - Carlotta Giorgi
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 48033 Ferrara, Italy; (C.G.); (S.M.); (M.P.); (P.P.)
| | - Sonia Missiroli
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 48033 Ferrara, Italy; (C.G.); (S.M.); (M.P.); (P.P.)
| | - Milena Gabbani
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
| | - Giuseppe Napoli
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
| | - Nicoletta Luca
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
| | - Daniela Mangiola
- Department of Clinical Oncology, Section of Medical Oncology, AULSS 9 Scaligera, 37045 Legnago, Italy; (J.G.); (M.M.); (D.M.)
| | - Marco Muraro
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
| | - Mariasole Perrone
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 48033 Ferrara, Italy; (C.G.); (S.M.); (M.P.); (P.P.)
| | - Paolo Pinton
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 48033 Ferrara, Italy; (C.G.); (S.M.); (M.P.); (P.P.)
| | - Francesco Fiorica
- Department of Clinical Oncology, Section of Medical Oncology, AULSS 9 Scaligera, 37045 Legnago, Italy; (J.G.); (M.M.); (D.M.)
- Department of Clinical Oncology, Section of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Legnago, Italy; (U.T.); (A.F.); (M.G.); (G.N.); (N.L.); (M.M.)
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8
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Han C, Xiao S, Xing Z, Xu X, Wang M, Han X, Adeli M, Qiu L, Ye L, Cheng C. NADPH Oxidases-Inspired Reactive Oxygen Biocatalysts with Electron-Rich Pt Sites to Potently Amplify Immune Checkpoint Blockade Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2407644. [PMID: 39400421 DOI: 10.1002/adma.202407644] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/19/2024] [Indexed: 10/15/2024]
Abstract
Clinical immune checkpoint blockade (ICB)-based immunotherapy of malignant tumors only elicits durable responses in a minority of patients, primarily due to the highly immunosuppressive tumor microenvironment. Although inducing immunogenic cell death (ICD) through reactive oxygen biocatalyst represents an attractive therapeutic strategy to amplify ICB, currently reported biocatalysts encounter insurmountable challenges in achieving high ROS-generating activity to induce potent ICD. Here, inspired by the natural catalytic characteristics of NADPH oxidases, the design of efficient, robust, and electron-rich Pt-based redox centers on the non-stoichiometric W18O49 substrates (Pt─WOx) to serve as bioinspired reactive oxygen biocatalysts to potently activate the ICD, which eventually enhance cancer immune responses and amplifies the ICB-based immunotherapy is reported. These studies demonstrate that the Pt─WOx exhibits rapid electron transfer capability and can promote the formation of electron-rich and low oxophilic Pt redox centers for superior reactive oxygen biocatalysis, which enables the Pt─WOx-based inducers to trigger endoplasmic reticulum stress directly and stimulate immune responses potently for amplifying the anti-PD-L1-based ICB therapy. This bioinspired design provides a straightforward strategy to engineer efficient, robust, and electron-rich reactive oxygen biocatalysts and also opens up a new avenue to create efficient ICD inducers for primary/metastatic tumor treatments.
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Affiliation(s)
- Chuyi Han
- Department of Endodontics, Department of Orthodontics, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Sutong Xiao
- Department of Endodontics, Department of Orthodontics, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, 610041, China
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Zhenyu Xing
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Xiaohui Xu
- Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mao Wang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Xianglong Han
- Department of Endodontics, Department of Orthodontics, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Mohsen Adeli
- Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Takustr. 3, 14195, Berlin, Germany
- Department of Organic Chemistry, Faculty of Chemistry, Lorestan University, Khorramabad, 68137-17133, Iran
| | - Li Qiu
- Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ling Ye
- Department of Endodontics, Department of Orthodontics, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Chong Cheng
- Department of Endodontics, Department of Orthodontics, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
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9
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Catanzaro E, Beltrán-Visiedo M, Galluzzi L, Krysko DV. Immunogenicity of cell death and cancer immunotherapy with immune checkpoint inhibitors. Cell Mol Immunol 2025; 22:24-39. [PMID: 39653769 PMCID: PMC11685666 DOI: 10.1038/s41423-024-01245-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
While immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various malignancies, a large fraction of patients are refractory to ICIs employed as standalone therapeutics, necessitating the development of combinatorial treatment strategies. Immunogenic cell death (ICD) inducers have attracted considerable interest as combinatorial partners for ICIs, at least in part owing to their ability to initiate a tumor-targeting adaptive immune response. However, compared with either approach alone, combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity. Here, we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings, identify key factors that may explain discrepancies between preclinical and clinical findings, and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer.
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Affiliation(s)
- Elena Catanzaro
- Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Manuel Beltrán-Visiedo
- Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Lorenzo Galluzzi
- Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.
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10
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Galassi C, Chan TA, Vitale I, Galluzzi L. The hallmarks of cancer immune evasion. Cancer Cell 2024; 42:1825-1863. [PMID: 39393356 DOI: 10.1016/j.ccell.2024.09.010] [Citation(s) in RCA: 80] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/27/2024] [Accepted: 09/16/2024] [Indexed: 10/13/2024]
Abstract
According to the widely accepted "three Es" model, the host immune system eliminates malignant cell precursors and contains microscopic neoplasms in a dynamic equilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune escape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel "three Cs" conceptual framework: (1) camouflage, which hides cancer cells from immune recognition, (2) coercion, which directly or indirectly interferes with immune effector cells, and (3) cytoprotection, which shields malignant cells from immune cytotoxicity. Blocking the ability of neoplastic cells to evade the host immune system is crucial for increasing the efficacy of modern immunotherapy and conventional therapeutic strategies that ultimately activate anticancer immunosurveillance. Here, we review key hallmarks of cancer immune evasion under the "three Cs" framework and discuss promising strategies targeting such immunoevasive mechanisms.
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Affiliation(s)
- Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Timothy A Chan
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA; Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; National Center for Regenerative Medicine, Cleveland, OH, USA; Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Ilio Vitale
- Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
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11
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Lamy D, Mouillot P, Mariet A, Barnestein R, Quilot F, Fraisse C, Ghiringhelli F, Bonniaud P, Zouak A, Foucher P. Real-world comparison of chemo-immunotherapy and chemotherapy alone in the treatment of extensive-stage small-cell lung cancer. Respir Med Res 2024; 86:101125. [PMID: 39033607 DOI: 10.1016/j.resmer.2024.101125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/23/2024]
Abstract
INTRODUCTION Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma responsible for 200,000 deaths per year worldwide. Platinum-etoposide-based chemotherapy has been the standard of treatment for the past 40 years, with an overall survival of 10 months. Since 2019, the addition of immunotherapy (atezolizumab or durvalumab) to chemotherapy has become the standard of care for first-line treatment of extensive-stage SCLC following the demonstration of an improvement in overall survival in phase 3 studies. We aimed to evaluate the efficacy and safety of chemo-immunotherapy compared with chemotherapy alone in a "real-world" setting. METHODS Retrospective observational study including patients undergoing first-line treatment for extensive-stage SCLC between 2014 and 2022. We separated the study population into two arms (chemo-immunotherapy/chemotherapy). For each arm, progression-free survival (PFS), overall survival (OS) and serious side effects were collected. Associations between treatments and survival outcomes were adjusted for potential confounders. Consolidative palliative thoracic radiotherapy was introduced in the models as a time-dependent variable. RESULTS A total of 118 patients with a median age of 63 years were included. 65.2 % of patients were performance status 0 or 1. In univariate analysis, PFS and OS were not significantly different between the chemo-immunotherapy and chemotherapy alone groups (p = 0.70 and 0.24 respectively). In multivariate analysis, the addition of immunotherapy to chemotherapy was not significantly associated with better PFS (HR 0.76, IC (0.49 - 1.19), p = 0.23), but it was significantly associated with better OS (HR 0.61, IC (0.38 - 0.98), p = 0.04). Consolidative palliative thoracic radiotherapy (time-dependent variable), when applied (almost only in the chemotherapy alone group), was significantly associated with better PFS and OS. DISCUSSION In this real-world study, chemo-immunotherapy was associated with slightly better OS compared to chemotherapy alone as a first-line treatment in ES-SCLC patients in multivariate analysis, which is not explained by a benefit in PFS. However, consolidative palliative thoracic radiotherapy seems to be significantly associated with better OS and PFS, suggesting that we should also consider using it in patients receiving chemo-immunotherapy.
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Affiliation(s)
- D Lamy
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France
| | - P Mouillot
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France; University of Burgundy, Faculty of Medicine and Pharmacy, Dijon, France; INSERM U1231 CTM, Labex LIPSTIC and label of excellence from la Ligue National contre le cancer, France
| | - A Mariet
- University of Burgundy, Faculty of Medicine and Pharmacy, Dijon, France; CHU Dijon Bourgogne, Service de Biostatistiques et d'information médicale, Dijon, France; INSERM, Université de Bourgogne, CHU Dijon Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France; CHU Dijon-Bourgogne, ResAM, Dijon, France
| | - R Barnestein
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France
| | - F Quilot
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France
| | - C Fraisse
- CHU Dijon-Bourgogne, ResAM, Dijon, France
| | - F Ghiringhelli
- University of Burgundy, Faculty of Medicine and Pharmacy, Dijon, France; CHU Dijon-Bourgogne, ResAM, Dijon, France; INSERM U1231 CTM, Labex LIPSTIC and label of excellence from la Ligue National contre le cancer, France
| | - P Bonniaud
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France; University of Burgundy, Faculty of Medicine and Pharmacy, Dijon, France; INSERM U1231 CTM, Labex LIPSTIC and label of excellence from la Ligue National contre le cancer, France.
| | - A Zouak
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France
| | - P Foucher
- Service d'Oncologie Thoracique et Service de Pneumologie et Soins Intensifs Respiratoire, Hôpital Dijon-Bourgogne, Dijon, France
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12
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Fan J, Gillespie KP, Mesaros C, Blair IA. HMGB2-induced calreticulin translocation required for immunogenic cell death and ferroptosis of cancer cells are controlled by the nuclear exporter XPO1. Commun Biol 2024; 7:1234. [PMID: 39354146 PMCID: PMC11445383 DOI: 10.1038/s42003-024-06930-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 09/20/2024] [Indexed: 10/03/2024] Open
Abstract
Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) protein from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the cell nucleus into the extracellular milieu. We previously showed that cisplatin-mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin-mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is required for the CRT translocation. Furthermore, CT-HMGB2 is three orders of magnitude more potent at inducing CRT translocation than oxaliplatin.
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Affiliation(s)
- Jingqi Fan
- Penn/CHOP Center of Excellence in Friedreich's Ataxia, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kevin P Gillespie
- Penn/CHOP Center of Excellence in Friedreich's Ataxia, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clementina Mesaros
- Penn/CHOP Center of Excellence in Friedreich's Ataxia, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ian A Blair
- Penn/CHOP Center of Excellence in Friedreich's Ataxia, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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13
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Zhang LL, Zhang DJ, Shi JX, Huang MY, Yu JM, Chen XJ, Wei X, Zou L, Lu JJ. Immunogenic cell death inducers for cancer therapy: An emerging focus on natural products. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155828. [PMID: 38905847 DOI: 10.1016/j.phymed.2024.155828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/03/2024] [Accepted: 06/12/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND Immunogenic cell death (ICD) is a specific form of regulated cell death induced by a variety of stressors. During ICD, the dying cancer cells release damage-associated molecular patterns (DAMPs), which promote dendritic cell maturation and tumor antigen presentation, subsequently triggering a T-cell-mediated anti-tumor immune response. In recent years, a growing number of studies have demonstrated the potential of natural products to induce ICD and enhance tumor cell immunogenicity. Moreover, there is an increasing interest in identifying new ICD inducers from natural products. PURPOSE This study aimed to emphasize the potential of natural products and their derivatives as ICD inducers to promote research on using natural products in cancer therapy and provide ideas for future novel immunotherapies based on ICD induction. METHOD This review included a thorough search of the PubMed, Web of Science, Scopus, and Google Scholar databases to identify natural products with ICD-inducing capabilities. A comprehensive search for clinical trials on natural ICD inducers was also conducted using ClinicalTrials.gov, as well as the approved patents using the Espacenet and CNKI Patent Database. RESULTS Natural compounds that induce ICD can be categorized into several groups, such as polyphenols, flavonoids, terpenoids, and alkaloids. Natural products can induce the release of DAMPs by triggering endoplasmic reticulum stress, activation of autophagy-related pathways, and reactive oxygen species generation, etc. Ultimately, they activate anti-tumor immune response and improve the efficacy of cancer treatments. CONCLUSION A growing number of ICD inducers from natural products with promising anti-cancer potential have been identified. The detailed information presented in this review will contribute to the further development of natural ICD inducers and cancer treatment strategies based on ICD-induced responses.
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Affiliation(s)
- Le-Le Zhang
- School of Basic Medical Sciences, Chengdu University, Chengdu 610106, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China
| | - Du-Juan Zhang
- College of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Jia-Xin Shi
- College of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Mu-Yang Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Jia-Mei Yu
- College of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Xu-Jia Chen
- College of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Xiao Wei
- School of Basic Medical Sciences, Chengdu University, Chengdu 610106, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Sichuan Engineering & Technology Research Center of Coarse Cereal Industrialization, Chengdu University, Chengdu 610106, China.
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, China.
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Guo Q, Wang X, Zhai Y, Dong Y, He Q. Oxaliplatin activates P53/miR-34a/survivin axis in inhibiting the progression of gastric cancer cells. Immun Inflamm Dis 2024; 12:e70004. [PMID: 39254476 PMCID: PMC11386343 DOI: 10.1002/iid3.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/31/2024] [Accepted: 08/08/2024] [Indexed: 09/11/2024] Open
Abstract
INTRODUCTION The purpose of this research was to determine how the P53/microRNA-34a (miR-34a)/survivin pathway contributes to oxaliplatin-induced (L-OHP) cell inhibition in gastric cancer. METHODS The BGC-823 gastric cancer cells were selected, and we examined their viability following treatment with L-OHP at different concentrations and time periods. The expression levels of miR-34a, P53, and survivin in the cells were determined. RESULTS In the 12- and 24-h groups, drug concentration of 15 μg/cm² (p < .005 in both) significantly lowered cell viability. In comparison to the control group, miR-34a mRNA expression, P53 mRNA expression, and protein expression were all significantly greater in the 24-h group (p = .0324, p = .0069, p = .0260, respectively), but survivin mRNA and protein expressions were significantly lower than those in the control group (p = .0338, p = .0032, respectively). There was a significant decrease in gastric cancer cells in the miR-34a overexpression group (p = .0020), a significant increase in P53 mRNA and protein expression compared to the control group (p = .0080, p = .0121, respectively), and a significant decrease in survivin mRNA and protein expression compared to the control group. (p = .0213, p = .0069, respectively). CONCLUSION Oxaliplatin inhibits tumor growth, invasion, and metastasis by upregulating miR-34a, activating the expression of the upstream P53 gene, and driving the downregulation of survivin (P53/miR-34a/survivin axis) in BGC-823 gastric cancer cells.
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Affiliation(s)
- Qiang Guo
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Baotou Medical CollegeBaotouChina
- Department of Gastrointestinal SurgeryQi Lu Hospital of Shandong UniversityJinanChina
| | - Xin‐Yuan Wang
- Department of General SurgeryHeNan RongJun HospitalXinxiangChina
| | - Yan‐Chang Zhai
- Department of Gastrointestinal SurgeryQi Lu Hospital of Shandong UniversityJinanChina
| | - Yong‐Wei Dong
- Department of Gastrointestinal SurgeryQi Lu Hospital of Shandong UniversityJinanChina
| | - Qing‐Si He
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Baotou Medical CollegeBaotouChina
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15
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Dutra MJ, Malta IS, de Almeida Lança ML, de Vasconcellos LMR, Adorno-Farias D, Jara JA, Kaminagakura E. Effects of artemisinin and cisplatin on the malignant progression of oral leukoplakia. In vitro and in vivo study. J Cancer Res Clin Oncol 2024; 150:390. [PMID: 39154308 PMCID: PMC11330948 DOI: 10.1007/s00432-024-05924-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 08/12/2024] [Indexed: 08/19/2024]
Abstract
OBJECTIVES Chemoprevention can be a treatment for potentially malignant lesions (PMLs). We aimed to evaluate whether artemisinin (ART) and cisplatin (CSP) are associated with apoptosis and immunogenic cell death (ICD) in vitro, using oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cell lines, and whether these compounds prevent OL progression in vivo. METHODS Normal keratinocytes (HaCat), Dysplastic oral cells (DOK), and oral squamous cell carcinoma (SCC-180) cell lines were treated with ART, CSP, and ART + CSP to analyze cytotoxicity, genotoxicity, cell migration, and increased expression of proteins related to apoptosis and ICD. Additionally, 41 mice were induced with OL using 4NQO, treated with ART and CSP, and their tongues were histologically analyzed. RESULTS In vitro, CSP and CSP + ART showed dose-dependent cytotoxicity and reduced SCC-180 migration. No treatment was genotoxic, and none induced expression of proteins related to apoptosis and ICD; CSP considerably reduced High-mobility group box-1 (HMGB-1) protein expression in SCC-180. In vivo, there was a delay in OL progression with ART and CSP treatment; however, by the 16th week, only CSP prevented progression to OSCC. CONCLUSION Expression of proteins related to ICD and apoptosis did not increase with treatments, and CSP was shown to reduce immunogenic pathways in SCC-180, while reducing cell migration. ART did not prevent the malignant progression of OL in vivo; CSP did despite significant adverse effects.
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Affiliation(s)
- Mateus José Dutra
- Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, University of São Paulo State, Avenue Engenheiro Francisco José Longo, 777, São José dos Campos, São Paulo, 12245-000, Brazil
| | - Isabella Souza Malta
- Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, University of São Paulo State, Avenue Engenheiro Francisco José Longo, 777, São José dos Campos, São Paulo, 12245-000, Brazil
| | - Maria Leticia de Almeida Lança
- Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, University of São Paulo State, Avenue Engenheiro Francisco José Longo, 777, São José dos Campos, São Paulo, 12245-000, Brazil
| | - Luana Marotta Reis de Vasconcellos
- Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, University of São Paulo State, Avenue Engenheiro Francisco José Longo, 777, São José dos Campos, São Paulo, 12245-000, Brazil
| | - Daniela Adorno-Farias
- Oral Medicine and Pathology Department, School of Dentistry, Universidad de Chile, Santiago, Chile
| | - José Antonio Jara
- Faculty of Dentistry, Institute for Research in Dental Sciences, Universidad de Chile, Santiago, Chile
| | - Estela Kaminagakura
- Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, University of São Paulo State, Avenue Engenheiro Francisco José Longo, 777, São José dos Campos, São Paulo, 12245-000, Brazil.
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Li Y, Ma P, Li J, Wu F, Guo M, Zhou E, Song S, Wang S, Zhang S, Jin Y. Dihydroartemisinin restores the immunogenicity and enhances the anticancer immunosurveillance of cisplatin by activating the PERK/eIF2α pathway. Cell Biosci 2024; 14:100. [PMID: 39090653 PMCID: PMC11295430 DOI: 10.1186/s13578-024-01254-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 05/24/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice. METHODS Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo. RESULTS Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo. CONCLUSIONS We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.
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Affiliation(s)
- Yumei Li
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pei Ma
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jingxia Li
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Wu
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengfei Guo
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - E Zhou
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Siwei Song
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sufei Wang
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Zhang
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yang Jin
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
- The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Province Engineering Research Center for Tumor-Targeted Biochemotherapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Denison M, Ullrich A, Herroon MK, Mecca S, Turro C, Podgorski I, Gibson H, Kodanko JJ. Ru(II)-Photoactive Agents for Targeting ER Stress and Immunogenic Cell Death. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.18.604104. [PMID: 39091867 PMCID: PMC11291038 DOI: 10.1101/2024.07.18.604104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Immunotherapy has emerged as a promising avenue for cancer treatment by bolstering the immune system's ability to recognize and attack cancer cells. Photodynamic therapy shows potential in enhancing antitumor immunity, though the mechanisms behind its success are not fully understood. In this manuscript, we investigate two previously reported green light activated PCT/PDT agents where compound 2 - [Ru(tpy)(Me2bpy)( 3 )] 2+ , (tpy = 2,2':6',2''- terpyridine, Me2bpy = 6,6'-dimethyl-2,2'-bipyridine, 3 = pyridyl-BODIPY-I2,) - shows remarkable photoselectivity in assays containing both 2D cancer cells and 3D cocultures containing BALB/c macrophages and 4T1 murine breast cancer cells. Through flow cytometry and protein analysis, we found complex 2 displays superior evidence of induced endoplasmic reticulum (ER) stress markers and indicators of immunogenic cell death (ICD) compared to its ligand 3 , despite its weaker photoselectivity. Most importantly, these results were supported by in vivo studies where 2 produced anti-tumor immunity against the 4T1 tumor model in BALB/c mice. Complete tumor elimination was achieved in 2/8 mice, and these mice were both protected against a subsequent contralateral rechallenge and showed increased ex vivo peripheral tumor antigen-specific recall, suggesting memory T cells are induced by 2 . Signatures of M1 macrophage polarization were also evident in tumor tissue from the remaining 6/8 mice treated with 2 compared to untreated tumors. These findings demonstrate Ru(II) complexation plays a critical role in ER targeting which triggers ICD, highlighting the potential of Ru(II) agents as future in situ tumor vaccines.
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Mentucci FM, Romero Nuñez EA, Ercole A, Silvetti V, Dal Col J, Lamberti MJ. Impact of Genomic Mutation on Melanoma Immune Microenvironment and IFN-1 Pathway-Driven Therapeutic Responses. Cancers (Basel) 2024; 16:2568. [PMID: 39061208 PMCID: PMC11274745 DOI: 10.3390/cancers16142568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors.
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Affiliation(s)
- Fátima María Mentucci
- Departamento de Biología Molecular, INBIAS, Universidad Nacional de Río Cuarto, Río Cuarto X5800BIA, Argentina; (F.M.M.); (V.S.)
| | - Elisa Ayelén Romero Nuñez
- Departamento de Biología Molecular, INBIAS, Universidad Nacional de Río Cuarto, Río Cuarto X5800BIA, Argentina; (F.M.M.); (V.S.)
| | - Agustina Ercole
- Departamento de Biología Molecular, INBIAS, Universidad Nacional de Río Cuarto, Río Cuarto X5800BIA, Argentina; (F.M.M.); (V.S.)
| | - Valentina Silvetti
- Departamento de Biología Molecular, INBIAS, Universidad Nacional de Río Cuarto, Río Cuarto X5800BIA, Argentina; (F.M.M.); (V.S.)
| | - Jessica Dal Col
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy;
| | - María Julia Lamberti
- Departamento de Biología Molecular, INBIAS, Universidad Nacional de Río Cuarto, Río Cuarto X5800BIA, Argentina; (F.M.M.); (V.S.)
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Yan C, Zhao Y, Liu X, Jiang Y, Li Q, Yang L, Li X, Luo K. Self-Delivery Nanobooster to Enhance Immunogenic Cell Death for Cancer Chemoimmunotherapy. ACS APPLIED MATERIALS & INTERFACES 2024; 16:33169-33181. [PMID: 38915234 DOI: 10.1021/acsami.4c06149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Inducing immunogenic cell death (ICD) is a promising strategy for cancer immunotherapy. Shikonin (SHK), a naphthoquinone compound from Lithospermum erythrorhizon, can stimulate antitumor immunity by inducing ICD. Nevertheless, the immunogenicity of tumor cells killed by SHK is weak. Endoplasmic reticulum (ER) stress is an important intracellular pathway of the ICD effect. Curcumin (CUR) can directly induce ER stress by disrupting Ca2+ homeostasis, which might enhance SHK-induced ICD effect. A self-delivery ICD effect nanobooster (CS-PEG NPs) was developed by the self-assembly of SHK (ICD inducer) and CUR (ICD enhancer) with the assistance of DSPE-PEG2K for cancer chemoimmunotherapy. CS-PEG NPs possessed effective CT26 tumor cell cellular uptake and tumor accumulation ability. Moreover, enhanced cytotoxicity against tumor cells and apoptosis promotion were achieved due to the synergistic effect of CUR and SHK. Notably, CS-PEG NPs induced obvious Ca2+ homeostasis disruption, ER stress, and ICD effect. Subsequently, the neoantigens produced by the robust ICD effect in vivo promoted dendritic cell maturation, which further recruited and activated cytotoxic T lymphocytes. Superior antitumor efficacy and systemic antitumor immunity were observed in the CT26-bearing BALB/c mouse model without side effects in major organs. This study offers a promising self-delivery nanobooster to induce strong ICD effect and antitumor immunity for cancer chemoimmunotherapy.
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Affiliation(s)
- Chunmei Yan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuxin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaolian Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yingjie Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Lu Yang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Kaipei Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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Wang C, Zhang M, Peng J, Zhang M, Lu C, Qi X, Luo Q, Wang Y, Li G. Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155504. [PMID: 38452404 DOI: 10.1016/j.phymed.2024.155504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/24/2024] [Accepted: 02/27/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system. PURPOSE To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity. METHODS Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting. RESULTS PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses. CONCLUSIONS This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.
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Affiliation(s)
- Congwen Wang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Mingxing Zhang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Jing Peng
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Meng Zhang
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Chong Lu
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Xingling Qi
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China
| | - Qingyan Luo
- Department of Anaesthesiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China
| | - Yumeng Wang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China.
| | - Guiling Li
- Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China.
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Yang Q, Yang G, Wu Y, Zhang L, Song Z, Yang D. Bioinformatics analysis and validation of genes related to paclitaxel's anti-breast cancer effect through immunogenic cell death. Heliyon 2024; 10:e28409. [PMID: 38560098 PMCID: PMC10979210 DOI: 10.1016/j.heliyon.2024.e28409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/04/2024] Open
Abstract
Research indicated that Paclitaxel (PTX) can induce immunogenic cell death (ICD) through immunogenic modulation. However, the combination of PTX and ICD has not been extensively studied in breast cancer (BRCA). The TCGA-BRCA and GSE20685 datasets were enrolled in this study. Samples from the TCGA-BRCA dataset were consistently clustered based on selected immunogenic cell death-related genes (ICD-RGs). Next, candidate genes were obtained by overlapping differentially expressed genes (DEGs) between BRCA and normal groups, intersecting genes common to DEGs between cluster1 and cluster2 and hub module genes, and target genes of PTX from five databases. The univariate Cox algorithm and the least absolute shrinkage and selection operator (LASSO) were performed to obtain biomarkers and build a risk model. Following observing the immune microenvironment in differential risk subgroups, single-gene gene set enrichment analysis (GSEA) was carried out in all biomarkers. Finally, the expression of biomarkers was analyzed. Enrichment analysis showed that 626 intersecting genes were linked with inflammatory response. Further five biomarkers (CHI3L1, IL18, PAPLN, SH2D2A, and UBE2L6) were identified and a risk model was built. The model's performance was validated using GSE20685 dataset. Furthermore, the biomarkers were enriched with adaptive immune response. Lastly, the experimental results indicated that the alterations in IL18, SH2D2A, and CHI3L1 expression after treatment matched those in the public database. In this study, Five PTX-ICD-related biomarkers (CHI3L1, IL18, PAPLN, SH2D2A, and UBE2L6) were identified to aid in predicting BRCA treatment outcomes.
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Affiliation(s)
- Qianmei Yang
- School of Pharmaceutical Science & Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China
- Yunnan College of Modern Biomedical Industry, Kunming, Yunnan, 650500, PR China
| | - Guimei Yang
- School of Pharmaceutical Science & Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China
- Yunnan College of Modern Biomedical Industry, Kunming, Yunnan, 650500, PR China
| | - Yi Wu
- Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, Yunnan, 650500, PR China
| | - Lun Zhang
- School of Pharmaceutical Science & Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China
| | - Zhuoyang Song
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China
| | - Dan Yang
- School of Pharmaceutical Science & Yunnan Provincial Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, PR China
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Blair I, Fan J, Gillespie K, Mesaros C. Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1. RESEARCH SQUARE 2024:rs.3.rs-4009459. [PMID: 38496553 PMCID: PMC10942558 DOI: 10.21203/rs.3.rs-4009459/v2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the nucleus into the extracellular milieu. We previously showed that cisplatin mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is responsible for translocation of CRT to the plasma membrane. CT-HMGB2 is three orders of magnitude more potent than oxaliplatin at inducing CRT translocation. Inhibition of HMGB1 and HMGB2 secretion and/or their activation of nuclear factor-kappa B (NF-kB) has potential utility for treating cardiovascular, and neurodegenerative diseases; whereas CT-HMGB2 could augment therapeutic approaches to cancer treatment.
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23
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Blair I, Fan J, Gillespie K, Mesaros C. Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1. RESEARCH SQUARE 2024:rs.3.rs-4009459. [PMID: 38496553 PMCID: PMC10942558 DOI: 10.21203/rs.3.rs-4009459/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the nucleus into the extracellular milieu. We previously showed that cisplatin mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is responsible for translocation of CRT to the plasma membrane. CT-HMGB2 is three orders of magnitude more potent than oxaliplatin at inducing CRT translocation. Inhibition of HMGB1 and HMGB2 secretion and/or their activation of nuclear factor-kappa B (NF-kB) has potential utility for treating cardiovascular, and neurodegenerative diseases; whereas CT-HMGB2 could augment therapeutic approaches to cancer treatment.
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Li X, Cai J, Zhang H, Sun S, Zhao S, Wang Z, Nie X, Xu C, Zhang Y, Xiao H. A Trisulfide Bond Containing Biodegradable Polymer Delivering Pt(IV) Prodrugs to Deplete Glutathione and Donate H 2S to Boost Chemotherapy and Antitumor Immunity. ACS NANO 2024; 18:7852-7867. [PMID: 38437513 DOI: 10.1021/acsnano.3c06194] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2024]
Abstract
The clinical application of cisplatin (CisPt) is limited by its dose-dependent toxicity. To overcome this, we developed reduction-responsive nanoparticles (NP(3S)s) for the targeted delivery of a platinum(IV) (Pt(IV)) prodrug to improve efficacy and reduce the toxicity. NP(3S)s could release Pt(II) and hydrogen sulfide (H2S) upon encountering intracellular glutathione, leading to potent anticancer effects. Notably, NP(3S)s induced DNA damage and activated the STING pathway, which is a known promoter for T cell activation. Comparative RNA profiling revealed that NP(3S)s outperformed CisPt in enhancing T cell immunity, antitumor immunity, and oxidative stress pathways. In vivo experiments showed that NP(3S)s accumulated in tumors, promoting CD8+ T cell infiltration and boosting antitumor immunity. Furthermore, NP(3S)s exhibited robust in vivo anticancer efficacy while minimizing the CisPt-induced liver toxicity. Overall, the results indicate NP(3S)s hold great promise for clinical translation due to their low toxicity profile and potent anticancer activity.
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Affiliation(s)
- Xinyi Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hanchen Zhang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Si Sun
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Simei Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zehua Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chun Xu
- School of Dentistry, The University of Queensland, Brisbane 4006, Australia
| | - Yuan Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, University of Chinese Academy of Sciences, Beijing 100049, China
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Jin S, Guo Y, Wang X. Development of Platinum Complexes for Tumor Chemoimmunotherapy. Chemistry 2024; 30:e202302948. [PMID: 38171804 DOI: 10.1002/chem.202302948] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Indexed: 01/05/2024]
Abstract
Platinum complexes are potential antitumor drugs in chemotherapy. Their impact on tumor treatment could be greatly strengthened by combining with immunotherapy. Increasing evidences indicate that the antitumor activity of platinum complexes is not limited to chemical killing effects, but also extends to immunomodulatory actions. This review introduced the general concept of chemoimmunotherapy and summarized the progress of platinum complexes as chemoimmunotherapeutic agents in recent years. Platinum complexes could be developed into inducers of immunogenic cell death, blockers of immune checkpoint, regulators of immune signaling pathway, and modulators of tumor immune microenvironment, etc. The synergy between chemotherapeutic and immunomodulatory effects reinforces the antitumor activity of platinum complexes, and helps them circumvent the drug resistance and systemic toxicity. The exploration of platinum complexes for chemoimmunotherapy may create new opportunities to revive the discovery of metal anticancer drugs.
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Affiliation(s)
- Suxing Jin
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, 210023, P. R. China
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, P. R. China
| | - Yan Guo
- School of Materials and Chemical Engineering, Henan University of Urban Construction, Pingdingshan, 467036, Henan, P. R. China
| | - Xiaoyong Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, P. R. China
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26
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Hengst JA, Nduwumwami AJ, Sharma A, Yun JK. Fanning the Flames of Endoplasmic Reticulum (ER) Stress: Can Sphingolipid Metabolism Be Targeted to Enhance ER Stress-Associated Immunogenic Cell Death in Cancer? Mol Pharmacol 2024; 105:155-165. [PMID: 38164594 PMCID: PMC10877730 DOI: 10.1124/molpharm.123.000786] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 01/03/2024] Open
Abstract
The three arms of the unfolded protein response (UPR) surveil the luminal environment of the endoplasmic reticulum (ER) and transmit information through the lipid bilayer to the cytoplasm to alert the cell of stress conditions within the ER lumen. That same lipid bilayer is the site of de novo synthesis of phospholipids and sphingolipids. Thus, it is no surprise that lipids are modulated by and are modulators of ER stress. Given that sphingolipids have both prosurvival and proapoptotic effects, they also exert opposing effects on life/death decisions in the face of prolonged ER stress detected by the UPR. In this review, we will focus on several recent studies that demonstrate how sphingolipids affect each arm of the UPR. We will also discuss the role of sphingolipids in the process of immunogenic cell death downstream of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiating factor 2α (eIF2α) arm of the UPR. Furthermore, we will discuss strategies to target the sphingolipid metabolic pathway that could potentially act synergistically with agents that induce ER stress as novel anticancer treatments. SIGNIFICANCE STATEMENT: This review provides the readers with a brief discussion of the sphingolipid metabolic pathway and the unfolded protein response. The primary focus of the review is the mechanism(s) by which sphingolipids modulate the endoplasmic reticulum (ER) stress response pathways and the critical role of sphingolipids in the process of immunogenic cell death associated with the ER stress response.
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Affiliation(s)
- Jeremy A Hengst
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| | - Asvelt J Nduwumwami
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| | - Arati Sharma
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| | - Jong K Yun
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
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Heiser RA, Cao AT, Zeng W, Ulrich M, Younan P, Anderson ME, Trueblood ES, Jonas M, Thurman R, Law CL, Gardai SJ. Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity. Mol Cancer Ther 2024; 23:68-83. [PMID: 37775098 PMCID: PMC10762337 DOI: 10.1158/1535-7163.mct-23-0118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 08/07/2023] [Accepted: 09/26/2023] [Indexed: 10/01/2023]
Abstract
Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the "gold-standard" test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B-cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous Epstein-Barr virus-reactive CD8+ T cells potentiating the activity of anti-PD-1 therapy. Together, these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.
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Hu Q, Wang S, Cheng R, Liu Y, Chang Z, Huang Y, Chen Y, Luo X, Zhou L, Wang B, Gao Y, Chen H, Liu R, Zhang L. Tannins in Phyllanthus emblica L. improves cisplatin efficacy in lung cancer cells by boosting endoplasmic reticulum stress to trigger immunogenic cell death. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155219. [PMID: 38056150 DOI: 10.1016/j.phymed.2023.155219] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/08/2023] [Accepted: 11/13/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Lung cancer is one of the deadliest cancers world-wide and immunotherapy has been considered as a promising therapeutic strategy. Previously, our study found that tannins in Phyllanthus emblica L. (PTF) could inhibit the growth of tumor by activating the immune response in liver cancer, and also exhibited a cytotoxicity on human lung cancer cells A549, H460, H1703 in vitro. OBJECTIVE To explore whether PTF inhibited the growth of lung cancer through its immune-regulating function and to clarify underlying mechanisms. METHODS The induction of immunogenic cell death (ICD) were characterized by calreticulin exposure, extracellular ATP secretion, and High Mobility Group Box 1(HMGB1) release both in vivo using LLC-derived xenograft tumor model and in vitro using both mouse LLC and human A549 cancer cells. RESULTS PTF inhibited lung cancer cells growth and tumorigenesis in vivo/vitro and promoted anti-tumor immune responses. We further found that PTF could induce ICD, which then activated Type I interferon responses and CXCL9/10-mediated chemotaxis. Mechanistically, PTF induced the formation of intracellular protein aggregates and following activation of PERK/ATF4/CHOP-dependent endoplasmic reticulum stress-related ICD. Moreover, PTF improved the antitumor efficacy of cisplatin by inducing ICD both in vitro and in vivo. Finally, we screened out 5 components from PTF, including gallocatechin, gallic acid, methyl gallate, ethyl gallate and ellagic acid, which could induce ICD in vitro and might be considered as the potential antitumor pharmacodynamic substances. CONCLUSION In conclusion, PTF inhibits the growth of lung cancer by triggering ICD and remodeling the tumor microenvironment, suggesting that PTF may have promising prospects as an adjacent immunotherapy for cancers.
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Affiliation(s)
- Qian Hu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Shukai Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Ruiyang Cheng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, PR China
| | - Yuqi Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Zihao Chang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Ya Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Yinxin Chen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Xiaowei Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Lipeng Zhou
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Baojin Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Ye Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Hongjiao Chen
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China.
| | - Lanzhen Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Road, Beijing 102488, PR China.
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Meng X, Ma F, Yu D. The diverse effects of cisplatin on tumor microenvironment: Insights and challenges for the delivery of cisplatin by nanoparticles. ENVIRONMENTAL RESEARCH 2024; 240:117362. [PMID: 37827371 DOI: 10.1016/j.envres.2023.117362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/11/2023] [Accepted: 10/09/2023] [Indexed: 10/14/2023]
Abstract
Cisplatin is a well-known platinum-based chemotherapy medication that is widely utilized for some malignancies. Despite the direct cytotoxic consequences of cisplatin on tumor cells, studies in the recent decade have revealed that cisplatin can also affect different cells and their secretions in the tumor microenvironment (TME). Cisplatin has complex impacts on the TME, which may contribute to its anti-tumor activity or drug resistance mechanisms. These regulatory effects of cisplatin play a paramount function in tumor growth, invasion, and metastasis. This paper aims to review the diverse impacts of cisplatin and nanoparticles loaded with cisplatin on cancer cells and also non-cancerous cells in TME. The impacts of cisplatin on immune cells, tumor stroma, cancer cells, and also hypoxia will be discussed in the current review. Furthermore, we emphasize the challenges and prospects of using cisplatin in combination with other adjuvants and therapeutic modalities that target TME. We also discuss the potential synergistic effects of cisplatin with immune checkpoint inhibitors (ICIs) and other agents with anticancer potentials such as polyphenols and photosensitizers. Furthermore, the potential of nanoparticles for targeting TME and better delivery of cisplatin into tumors will be discussed.
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Affiliation(s)
- Xinxin Meng
- Zhuji Sixth People's Hospital of Zhejiang Province, Zhuji, Zhejiang, 311801, China
| | - Fengyun Ma
- Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, 311800, China.
| | - Dingli Yu
- Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, 311800, China
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Huang J, Duan F, Xie C, Xu J, Zhang Y, Wang Y, Tang YP, Leung ELH. Microbes mediated immunogenic cell death in cancer immunotherapy. Immunol Rev 2024; 321:128-142. [PMID: 37553793 DOI: 10.1111/imr.13261] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 08/10/2023]
Abstract
Immunogenic cell death (ICD) is one of the 12 distinct cell death forms, which can trigger immune system to fight against cancer cells. During ICD, a number of cellular changes occur that can stimulate an immune response, including the release of molecules called damage-associated molecular patterns (DAMPs), signaling to immune cells to recognize and attack cancer cells. By virtue of their pivotal role in immune surveillance, ICD-based drug development has been a new approach to explore novel therapeutic combinations and personalized strategies in cancer therapy. Several small molecules and microbes can induce ICD-relevant signals and cause cancer cell death. In this review, we highlighted the role of microbe-mediate ICD in cancer immunotherapy and described the mechanisms through which microbes might serve as ICD inducers in cancer treatment. We also discussed current attempts to combine microbes with chemotherapy regimens or immune checkpoint inhibitors (ICIs) in the treatment of cancer patients. We surmise that manipulation of microbes may guide personalized therapeutic interventions to facilitate anticancer immune response.
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Affiliation(s)
- Jumin Huang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China
- MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), China
| | - Fugang Duan
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- NHC Key Laboratory of Medical Immunology, Peking University Health Science Center, Beijing, China
- Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, China
| | - Chun Xie
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China
- MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), China
| | - Jiahui Xu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China
- MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), China
| | - Yizhong Zhang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Dr. Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Yuwei Wang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi Province, China
| | - Yu-Ping Tang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi Province, China
| | - Elaine Lai-Han Leung
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China
- MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), China
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China
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31
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Park JH, Kim MS, Yun DH, Kim YC. Apoptosis/Necroptosis Inducing Thiazole-Containing Artificial Polypeptide for Immunogenic Cell Death of Cancer. ACS APPLIED BIO MATERIALS 2023; 6:5290-5300. [PMID: 38044569 DOI: 10.1021/acsabm.3c00581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Immunogenic cell death (ICD) has emerged as a promising approach to cancer immunotherapy. During ICD, cancer cell death and the release of damage-associated molecular pattern (DAMP) signals occur simultaneously. Increased production of reactive oxygen species (ROS) and severe endoplasmic reticulum stress are necessary for enhanced ICD. Furthermore, the levels of ROS and reduced glutathione (GSH) are involved in various cell death mechanisms. The thiazole ring structure has gained considerable interest as a functional moiety for anticancer agents. This study designed and synthesized a positively charged cell-penetrating polypeptide with a thiazole functional moiety (NS). The NS internalizes into the cancer cells through direct penetration and endo-lysosomal escape. The NS induces mitochondrial depolarization and ER stress in a concentration-dependent manner, leading to a significant ROS production and GSH depletion. Consequently, the ICD of cancer cells is activated, resulting in the release of DAMP signals. Furthermore, NS causes a shift in the cell death pathway from apoptosis to necroptosis as the concentration increases. In this study, we confirmed the possibility of NS as a promising ICD inducer that can be used while varying the concentration according to the cancer type.
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Affiliation(s)
- Jeong Ho Park
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291, Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Mun Sik Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291, Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Do Hyun Yun
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291, Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Yeu-Chun Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291, Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
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Huang X, Ren Q, Yang L, Cui D, Ma C, Zheng Y, Wu J. Immunogenic chemotherapy: great potential for improving response rates. Front Oncol 2023; 13:1308681. [PMID: 38125944 PMCID: PMC10732354 DOI: 10.3389/fonc.2023.1308681] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/15/2023] [Indexed: 12/23/2023] Open
Abstract
The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate anti-tumor immunity by inducing immunogenic cell death and durably eradicate tumors. This suggests that immunogenic chemotherapy holds great potential for improving response rates. However, chemotherapy in practice has only had limited success in inducing long-term survival or cure of cancers when used either alone or in combination with immunotherapy. We think that this is because the importance of dose, schedule, and tumor model dependence of chemotherapy-activated anti-tumor immunity is under-appreciated. Here, we review immune modulation function of representative chemotherapy agents and propose a model of immunogenic chemotherapy-induced long-lasting responses that rely on synergetic interaction between killing tumor cells and inducing anti-tumor immunity. We comb through several chemotherapy treatment schedules, and identify the needs for chemotherapy dose and schedule optimization and combination therapy with immunotherapy when chemotherapy dosage or immune responsiveness is too low. We further review tumor cell intrinsic factors that affect the optimal chemotherapy dose and schedule. Lastly, we review the biomarkers indicating responsiveness to chemotherapy and/or immunotherapy treatments. A deep understanding of how chemotherapy activates anti-tumor immunity and how to monitor its responsiveness can lead to the development of more effective chemotherapy or chemo-immunotherapy, thereby improving the efficacy of cancer treatment.
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Affiliation(s)
- Xiaojun Huang
- Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Qinghuan Ren
- Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Leixiang Yang
- Cancer Center, The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Center for Reproductive Medicine, Department of Genetic and Genomic Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Di Cui
- Cancer Center, The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Chenyang Ma
- Department of Internal Medicine of Traditional Chinese Medicine, The Second People’s Hospital of Xiaoshan District, Hangzhou, Zhejiang, China
| | - Yueliang Zheng
- Cancer Center, Emergency and Critical Care Center, Department of Emergency Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junjie Wu
- Cancer Center, The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Center for Reproductive Medicine, Department of Genetic and Genomic Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
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33
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Li J, Han X, Sun M, Li W, Yang G, Chen H, Guo B, Li J, Li X, Wang H. Caspase-9 inhibition triggers Hsp90-based chemotherapy-mediated tumor intrinsic innate sensing and enhances antitumor immunity. J Immunother Cancer 2023; 11:e007625. [PMID: 38056894 PMCID: PMC10711858 DOI: 10.1136/jitc-2023-007625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Antineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive. METHODS A rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models. RESULTS Heat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-β via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP-AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression. CONCLUSIONS Blockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8+ T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.
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Affiliation(s)
- Jingyang Li
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyu Han
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mayu Sun
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weida Li
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guanghuan Yang
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huiyi Chen
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bao Guo
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingquan Li
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoguang Li
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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34
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Yu X, Qi S, Cao F, Yang K, Li H, Peng K, Liu Z, Bai B, Buljan M, Chen X, Yu G. Fabrication of An Immunostimulatory Supramolecular Nanomedicine for Potent Cancer Chemoimmunotherapy. JACS AU 2023; 3:3181-3193. [PMID: 38034980 PMCID: PMC10685430 DOI: 10.1021/jacsau.3c00515] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023]
Abstract
Chemoimmunotherapy can boost strong antitumor immune responses by triggering immunogenic cell death (ICD), which highlights a promising prospect in clinical applications. However, current chemoimmunotherapy shows limited efficacy due to the low delivery efficiency and insufficient immunogenicity of available chemotherapeutic drugs. A supramolecular polymeric nanomedicine (Pt-Tu@NP) is herein reported using cucurbit[7]uril-based host-guest recognition and noncovalent self-assembly. Pt-Tu@NPs have excellent biodistribution and strongly evoke the endoplasmic reticulum stress-mediated ICD of tumor cells, triggering potent antitumor immune responses by promoting dendritic cell (DC) maturation and cytotoxic T cell infiltration. The coordinated butyrate promotes a positive feedback regulation between DCs and CD8+ T cells. Pt-Tu@NPs stimulate immune cold tumors into hot ones, working in synergy with an immune checkpoint blockade to effectively suppress tumor growth and metastasis, which suggests a promising approach for cancer chemoimmunotherapy.
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Affiliation(s)
- Xinyang Yu
- MOE
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
| | - Shaolong Qi
- MOE
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
| | - Fangfang Cao
- Yong
Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore
| | - Kai Yang
- MOE
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
| | - Hongjian Li
- School
of Medicine, Tsinghua University, Beijing 100084, P. R. China
| | - Kun Peng
- School
of Medicine, Tsinghua University, Beijing 100084, P. R. China
| | - Zhida Liu
- Shanxi
Academy of Advanced Research and Innovation, Taiyuan 030032, P. R. China
| | - Bing Bai
- MOE
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
| | - Marija Buljan
- Empa,
Swiss Federal Laboratories for Materials Science and Technology, 9014 St. Gallen, Switzerland
| | - Xiaoyuan Chen
- Yong
Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore
| | - Guocan Yu
- MOE
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
- School
of Medicine, Tsinghua University, Beijing 100084, P. R. China
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35
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Chou W, Sun T, Peng N, Wang Z, Chen D, Qiu H, Zhao H. Photodynamic Therapy-Induced Anti-Tumor Immunity: Influence Factors and Synergistic Enhancement Strategies. Pharmaceutics 2023; 15:2617. [PMID: 38004595 PMCID: PMC10675361 DOI: 10.3390/pharmaceutics15112617] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/28/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity towards tumor cells by activating photosensitizers (PSs) with light exposure to produce reactive oxygen species (ROS). Compared to traditional treatment strategies such as surgery, chemotherapy, and radiation therapy, PDT not only kills the primary tumors, but also effectively suppresses metastatic tumors by activating the immune response. However, the anti-tumor immune effects induced by PDT are influenced by several factors, including the localization of PSs in cells, PSs concentration, fluence rate of light, oxygen concentration, and the integrity of immune function. In this review, we systematically summarize the influence factors of anti-tumor immune effects mediated by PDT. Furthermore, an update on the combination of PDT and other immunotherapy strategies are provided. Finally, the future directions and challenges of anti-tumor immunity induced by PDT are discussed.
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Affiliation(s)
- Wenxin Chou
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (W.C.); (T.S.); (N.P.); (D.C.)
| | - Tianzhen Sun
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (W.C.); (T.S.); (N.P.); (D.C.)
| | - Nian Peng
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (W.C.); (T.S.); (N.P.); (D.C.)
| | - Zixuan Wang
- Department of Laser Medicine, the First Medical Center, PLA General Hospital, Beijing 100853, China;
| | - Defu Chen
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (W.C.); (T.S.); (N.P.); (D.C.)
| | - Haixia Qiu
- Department of Laser Medicine, the First Medical Center, PLA General Hospital, Beijing 100853, China;
| | - Hongyou Zhao
- School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China; (W.C.); (T.S.); (N.P.); (D.C.)
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36
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Li T, Zeng Z, Fan C, Xiong W. Role of stress granules in tumorigenesis and cancer therapy. Biochim Biophys Acta Rev Cancer 2023; 1878:189006. [PMID: 37913942 DOI: 10.1016/j.bbcan.2023.189006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 09/24/2023] [Accepted: 10/16/2023] [Indexed: 11/03/2023]
Abstract
Stress granules (SGs) are membrane-less organelles that cell forms via liquid-liquid phase separation (LLPS) under stress conditions such as oxidative stress, ER stress, heat shock and hypoxia. SG assembly is a stress-responsive mechanism by regulating gene expression and cellular signaling pathways. Cancer cells face various stress conditions in tumor microenvironment during tumorigenesis, while SGs contribute to hallmarks of cancer including proliferation, invasion, migration, avoiding apoptosis, metabolism reprogramming and immune evasion. Here, we review the connection between SGs and cancer development, the limitation of SGs on current cancer therapy and promising cancer therapeutic strategies targeting SGs in the future.
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Affiliation(s)
- Tiansheng Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Chunmei Fan
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China; Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
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Wu Y, Wang C, Yan Y, Hao Y, Liu B, Dong Z, Chen M, Zhu Y, Liu N, Feng L, Liu Z. Efferocytosis Nanoinhibitors to Promote Secondary Necrosis and Potentiate the Immunogenicity of Conventional Cancer Therapies for Improved Therapeutic Benefits. ACS NANO 2023; 17:18089-18102. [PMID: 37669546 DOI: 10.1021/acsnano.3c04884] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Efferocytosis of apoptotic cancer cells by tumor-associated macrophages or other phagocytes is reported to promote tumor immunosuppression by preventing them from secondary necrosis, which would lead to the release of intracellular components and thus enhanced immunogenicity. Therefore, current apoptosis-inducing cancer treatments (e.g., chemotherapy and radiotherapy) are less satisfactory in eliciting antitumor immunity. Herein, a nanoparticulate inhibitor of efferocytosis is prepared by encapsulating BMS777607, a hydrophobic inhibitor of receptors in macrophages responsible for phosphatidylserine-dependent efferocytosis, with biocompatible poly(lactic-co-glycolic acid) and its amphiphilic derivatives. The yielded nano-BMS can inhibit the efferocytosis of apoptotic cancer cells, thus redirecting them to immunogenic secondary necrosis. As a result, intratumorally injected nano-BMS is capable of activating both innate and adaptive antitumor immunity to achieve greatly improved therapeutic responses, when synergized with nonimmunogenic chemotherapy by cisplatin, immunogenic chemotherapy by oxaliplatin, or radiotherapy by external beams. Moreover, we further demonstrate that the inhalation of nano-BMS could significantly promote the efficacy of cisplatin chemotherapy to suppress tumor lung metastases. Therefore, this study highlights a general strategy to potentiate the immunogenicity of different cancer treatments by suppressing efferocytosis-propelled tumor immunosuppression, showing tremendous clinical potential in rescuing existing cancer therapies for more effective treatment.
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Affiliation(s)
- Yumin Wu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Chunjie Wang
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Yifan Yan
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Yu Hao
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Bo Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Ziliang Dong
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Minming Chen
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Yujie Zhu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Nanhui Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Liangzhu Feng
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
| | - Zhuang Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren' ai Road, Suzhou, Jiangsu 215123, People's Republic of China
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Yu S, Xiao H, Ma L, Zhang J, Zhang J. Reinforcing the immunogenic cell death to enhance cancer immunotherapy efficacy. Biochim Biophys Acta Rev Cancer 2023; 1878:188946. [PMID: 37385565 DOI: 10.1016/j.bbcan.2023.188946] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
Immunogenic cell death (ICD) has been a revolutionary modality in cancer treatment since it kills primary tumors and prevents recurrent malignancy simultaneously. ICD represents a particular form of cancer cell death accompanied by production of damage-associated molecular patterns (DAMPs) that can be recognized by pattern recognition receptors (PRRs), which enhances infiltration of effector T cells and potentiates antitumor immune responses. Various treatment methods can elicit ICD involving chemo- and radio-therapy, phototherapy and nanotechnology to efficiently convert dead cancer cells into vaccines and trigger the antigen-specific immune responses. Nevertheless, the efficacy of ICD-induced therapies is restrained due to low accumulation in the tumor sites and damage of normal tissues. Thus, researchers have been devoted to overcoming these problems with novel materials and strategies. In this review, current knowledge on different ICD modalities, various ICD inducers, development and application of novel ICD-inducing strategies are summarized. Moreover, the prospects and challenges are briefly outlined to provide reference for future design of novel immunotherapy based on ICD effect.
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Affiliation(s)
- Sihui Yu
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hongyang Xiao
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Li Ma
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jiawen Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Jiarong Zhang
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
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Mukherjee O, Rakshit S, Shanmugam G, Sarkar K. Role of chemotherapeutic drugs in immunomodulation of cancer. CURRENT RESEARCH IN IMMUNOLOGY 2023; 4:100068. [PMID: 37692091 PMCID: PMC10491645 DOI: 10.1016/j.crimmu.2023.100068] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023] Open
Abstract
The immune system has a variety of potential effects on a tumor microenvironment and the course of chemotherapy may vary according to that. Anticancer treatments can encourage the release of unwanted signals from senescent tumor cells or the removal of immune-suppressive cells, which can lead to immune system activation. Hence, by inducing an immunological response and conversely making cancer cells more vulnerable to immune attack, chemotherapeutic agents can destroy cancer cells. Furthermore, chemotherapy can activate anticancer immune effectors directly or indirectly by thwarting immunosuppressive pathways. Therefore, in this review, we discuss how chemotherapeutic agents take part in immunomodulation and the molecular mechanisms underlying them. We also focus on the importance of carefully addressing the conflicting effects of chemotherapy on immune responses when developing successful combination treatments based on chemotherapy and immune modulators.
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Affiliation(s)
- Oishi Mukherjee
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Sudeshna Rakshit
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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Lamichhane PP, Samir P. Cellular Stress: Modulator of Regulated Cell Death. BIOLOGY 2023; 12:1172. [PMID: 37759572 PMCID: PMC10525759 DOI: 10.3390/biology12091172] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/22/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023]
Abstract
Cellular stress response activates a complex program of an adaptive response called integrated stress response (ISR) that can allow a cell to survive in the presence of stressors. ISR reprograms gene expression to increase the transcription and translation of stress response genes while repressing the translation of most proteins to reduce the metabolic burden. In some cases, ISR activation can lead to the assembly of a cytoplasmic membraneless compartment called stress granules (SGs). ISR and SGs can inhibit apoptosis, pyroptosis, and necroptosis, suggesting that they guard against uncontrolled regulated cell death (RCD) to promote organismal homeostasis. However, ISR and SGs also allow cancer cells to survive in stressful environments, including hypoxia and during chemotherapy. Therefore, there is a great need to understand the molecular mechanism of the crosstalk between ISR and RCD. This is an active area of research and is expected to be relevant to a range of human diseases. In this review, we provided an overview of the interplay between different cellular stress responses and RCD pathways and their modulation in health and disease.
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Affiliation(s)
| | - Parimal Samir
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
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Zhang J, Du J, Jin Z, Qian J, Xu J. A novel immunogenic cell death signature for the prediction of prognosis and therapies in glioma. PeerJ 2023; 11:e15615. [PMID: 37456890 PMCID: PMC10348309 DOI: 10.7717/peerj.15615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
Glioma is a primary cranial malignancy with high recurrence rate, poor prognosis and high mortality. However, the roles of immunogenic cell death (ICD) in glioma remain unclear. Twenty ICD genes were analyzed to be differentially expressed between glioma tissues and non-tumor tissues in 371 glioma patients from The Cancer Genome Atlas (TCGA). Patients were classified into three subgroups via unsupervised clustering. Interestingly, the features of cell-infiltrating from three clusters were matched with three immune phenotypes. An applied scoring system was built depending on the expression of hub ICD-related genes. Notably, the ICD-related score was linked with immune checkpoints and the prognosis of glioma patients. In addition, the applied risk model could be used for the prediction of the effect of chemotherapy and immunotherapy for glioma patients. Furthermore, MYD88 was identified to play key roles in the risk model for glioma patients. MYD88 was specifically expressed in malignant cells and validated to correlate with cell proliferation and invasion. Ligand-receptor pairs are determined as novel communications indicating between immunocytes and malignant cells. Therefore, our research established an ICD-related score to investigate the potential effect to chemotherapy and immunotherapy for glioma patients and indicated that MYD88 was a key role in this risk model.
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Affiliation(s)
- Jianhua Zhang
- Department of Oncology, People’s Hospital of Chizhou, Chizhou, China
| | - Jin Du
- Department of Neurosurgery, People’s Hospital of Chizhou, Chizhou, China
| | - Zhihai Jin
- Department of Orthopedics, Handan First Hospital, Handan, China
| | - Jiang Qian
- Department of Oncology, People’s Hospital of Chizhou, Chizhou, China
| | - Jinfa Xu
- Department of Oncology, People’s Hospital of Chizhou, Chizhou, China
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Kongsomboonvech AK, García-López L, Njume F, Rodriguez F, Souza SP, Rosenberg A, Jensen KDC. Variation in CD8 T cell IFNγ differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16. Front Cell Infect Microbiol 2023; 13:1130965. [PMID: 37287466 PMCID: PMC10242045 DOI: 10.3389/fcimb.2023.1130965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 04/17/2023] [Indexed: 06/09/2023] Open
Abstract
Introduction Toxoplasma gondii induces a strong CD8 T cell response characterized by the secretion of IFNγ that promotes host survival during infection. The initiation of CD8 T cell IFNγ responses in vitro differs widely between clonal lineage strains of T. gondii, in which type I strains are low inducers, while types II and III strains are high inducers. We hypothesized this phenotype is due to a polymorphic "Regulator Of CD8 T cell Response" (ROCTR). Methods Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Naïve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for the endogenous and vacuolar TGD057 antigen, were measured for their ability to become activated, transcribe Ifng and produce IFNγ in response to T. gondii infected macrophages. Results Genetic mapping returned four non-interacting quantitative trait loci (QTL) with small effect on T. gondii chromosomes (chr) VIIb-VIII, X and XII. These loci encompass multiple gene candidates highlighted by ROP16 (chrVIIb-VIII), GRA35 (chrX), TgNSM (chrX), and a pair of uncharacterized NTPases (chrXII), whose locus we report to be significantly truncated in the type I RH background. Although none of the chromosome X and XII candidates bore evidence for regulating CD8 T cell IFNγ responses, type I variants of ROP16 lowered Ifng transcription early after T cell activation. During our search for ROCTR, we also noted the parasitophorous vacuole membrane (PVM) targeting factor for dense granules (GRAs), GRA43, repressed the response suggesting PVM-associated GRAs are important for CD8 T cell activation. Furthermore, RIPK3 expression in macrophages was an absolute requirement for CD8 T cell IFNγ differentiation implicating the necroptosis pathway in T cell immunity to T. gondii. Discussion Collectively, our data suggest that while CD8 T cell IFNγ production to T. gondii strains vary dramatically, it is not controlled by a single polymorphism with strong effect. However, early in the differentiation process, polymorphisms in ROP16 can regulate commitment of responding CD8 T cells to IFNγ production which may have bearing on immunity to T. gondii.
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Affiliation(s)
- Angel K. Kongsomboonvech
- Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, United States
- Quantitative Systems Biology Graduate Program, University of California, Merced, Merced, CA, United States
| | - Laura García-López
- Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, United States
- Quantitative Systems Biology Graduate Program, University of California, Merced, Merced, CA, United States
| | - Ferdinand Njume
- Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, United States
| | - Felipe Rodriguez
- Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, United States
| | - Scott P. Souza
- Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, United States
- Quantitative Systems Biology Graduate Program, University of California, Merced, Merced, CA, United States
| | - Alex Rosenberg
- The Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
| | - Kirk D. C. Jensen
- Department of Molecular and Cell Biology, University of California, Merced, Merced, CA, United States
- Health Sciences Research Institute, University of California, Merced, Merced, CA, United States
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Chen Q, Li C, Wang Q. Multifunctional Nano-Biomaterials for Cancer Therapy via Inducing Enhanced Immunogenic Cell Death. SMALL METHODS 2023; 7:e2201457. [PMID: 36703555 DOI: 10.1002/smtd.202201457] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/30/2022] [Indexed: 05/17/2023]
Abstract
Immunotherapy is considered to be one of the most promising methods to overcome cancer. Immunogenic cell death (ICD), as a special form of cell death that can trigger an antitumor immune response, has attracted increasing attention for cancer immunotherapy. Presently, ICD-mediating immunotherapy needs to overcome many hurdles including a lack of targeted delivery systems for ICD inducers, insufficient antitumor immunity, and the immunosuppressive tumor microenvironment. Recent research has demonstrated that nano-biomaterials exhibit unique biochemphysical properties at the nanoscale, providing a prospective approach to overcoming these obstacles. In this review, the authors first survey the occurrence, processes, and detection methods of ICD. Subsequently, the recent advances of nano-biomaterials applied to enhance ICD according to the key steps in the process of ICD, particularly with a focus on the mechanisms and lifting schemes are investigated. Finally, based on the achievement in the representative studies, the prospects and challenges of nanotechnology in ICD for cancer therapy are discussed to enable clinical translation.
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Affiliation(s)
- Qian Chen
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- North District of Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, China
| | - Chunyan Li
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Qiangbin Wang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
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Kesar U, Markelc B, Jesenko T, Ursic Valentinuzzi K, Cemazar M, Strojan P, Sersa G. Effects of Electrochemotherapy on Immunologically Important Modifications in Tumor Cells. Vaccines (Basel) 2023; 11:vaccines11050925. [PMID: 37243029 DOI: 10.3390/vaccines11050925] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Electrochemotherapy (ECT) is a clinically acknowledged method that combines the use of anticancer drugs and electrical pulses. Electrochemotherapy with bleomycin (BLM) can induce immunogenic cell death (ICD) in certain settings. However, whether this is ubiquitous over different cancer types and for other clinically relevant chemotherapeutics used with electrochemotherapy is unknown. Here, we evaluated in vitro in the B16-F10, 4T1 and CT26 murine tumor cell lines, the electrochemotherapy triggered changes in the ICD-associated damage-associated molecular patterns (DAMPs): Calreticulin (CRT), ATP, High Mobility Group Box 1 (HMGB1), and four immunologically important cellular markers: MHCI, MHC II, PD-L1 and CD40. The changes in these markers were investigated in time up to 48 h after ECT. We showed that electrochemotherapy with all three tested chemotherapeutics induced ICD-associated DAMPs, but the induced DAMP signature was cell line and chemotherapeutic concentration specific. Similarly, electrochemotherapy with CDDP, OXA or BLM modified the expression of MHC I, MHC II, PD-L1 and CD40. The potential of electrochemotherapy to change their expression was also cell line and chemotherapeutic concentration specific. Our results thus put the electrochemotherapy with clinically relevant chemotherapeutics CDDP, OXA and BLM on the map of ICD inducing therapies.
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Affiliation(s)
- Ursa Kesar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Bostjan Markelc
- Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
| | - Tanja Jesenko
- Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Katja Ursic Valentinuzzi
- Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
- Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Health Sciences, University of Primorska, 6310 Izola, Slovenia
| | - Primoz Strojan
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Department of Radiation Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia
| | - Gregor Sersa
- Department of Experimental Oncology, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Health Sciences, University of Ljubljana, 1000 Ljubljana, Slovenia
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Perez-Potti A, Rodríguez-Pérez M, Polo E, Pelaz B, Del Pino P. Nanoparticle-based immunotherapeutics: from the properties of nanocores to the differential effects of administration routes. Adv Drug Deliv Rev 2023; 197:114829. [PMID: 37121275 DOI: 10.1016/j.addr.2023.114829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/24/2023] [Accepted: 04/14/2023] [Indexed: 05/02/2023]
Abstract
The engagement with the immune system is one of the main cornerstones in the development of nanotechnologies for therapy and diagnostics. Recent advances have made possible the tuning of features like size, shape and biomolecular modifications that influence such interactions, however, the capabilities for immune modulation of nanoparticles are still not well defined and exploited. This review focuses on recent advances made in preclinical research for the application of nanoparticles to modulate immune responses, and the main features making them relevant for such applications. We review and discuss newest evidence in the field, which include in vivo experiments with an extensive physicochemical characterization as well as detailed study of the induced immune response. We emphasize the need of incorporating knowledge about immune response development and regulation in the design and application of nanoparticles, including the effect by parameters such as the administration route and the differential interactions with immune subsets.
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Affiliation(s)
- André Perez-Potti
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Manuel Rodríguez-Pérez
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Ester Polo
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Beatriz Pelaz
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
| | - Pablo Del Pino
- Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
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Wu PJ, Chiou HL, Hsieh YH, Lin CL, Lee HL, Liu IC, Ying TH. Induction of immunogenic cell death effect of licoricidin in cervical cancer cells by enhancing endoplasmic reticulum stress-mediated high mobility group box 1 expression. ENVIRONMENTAL TOXICOLOGY 2023. [PMID: 37013980 DOI: 10.1002/tox.23793] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/20/2023] [Accepted: 03/19/2023] [Indexed: 06/19/2023]
Abstract
Licoricidin (LCD) is an activity compound of the roots of Glycyrrhiza uralensis, which has therapeutic efficacy, including anti-virus, anti-cancer, and enhanced immunity in Traditional Chinese Medicine. Herein, this study aimed to clarify the effect of LCD on cervical cancer cells. In the present study, we found that LCD significantly inhibited cell viability via inducing cell apoptosis and companies with cleaved-PARP protein expression and caspase-3/-9 activity. Cell viability was markedly reversed these effects by pan-caspase inhibitor Z-VAD-FMK treatment. Furthermore, we showed that LCD-induced ER (endoplasmic reticulum) stress triggers upregulating the protein level of GRP78 (Bip), CHOP, and IRE1α, and subsequently confirmed the mRNA level by quantitative real-time polymerase chain reaction. In addition, LCD exhibited the release of danger-associated molecular patterns from cervical cancer cells, such as the release of high-mobility group box 1 (HMGB1), secretion of ATP, and exposure of calreticulin (CRT) on the cell surface, which led to immunogenic cell death (ICD). These results provide a novel foundation that LCD induces ICD via triggering ER stress in human cervical cancer cells. LCD might be an ICD inducer of immunotherapy in progressive cervical cancer.
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Affiliation(s)
- Pei-Ju Wu
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Hui-Ling Chiou
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chia-Liang Lin
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Hsiang-Lin Lee
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - I-Chun Liu
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Tsung-Ho Ying
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Luo H, Wang L, Zhang D, Sun Y, Wang S, Song S, Ge H. HA15 inhibits binding immunoglobulin protein and enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma. Cancer Sci 2023; 114:1697-1709. [PMID: 36582172 PMCID: PMC10067410 DOI: 10.1111/cas.15712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 12/20/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Proteomic profiling is a promising approach to identify novel predictors of radiation response. The present study aimed to identify potential biomarkers of radiation response by serum proteomics in esophageal squamous cell carcinoma (ESCC) patients and find efficacious therapeutic drugs to enhance the efficacy of radiation therapy (RT). Serum binding immunoglobulin protein (BIP) was identified and validated as a treatment response predictor in ESCC patients treated with RT. Novel BIP inhibitor HA15 showed antitumor activity in ESCC cells by viability assay. Tumor cell colony formation and apoptosis assay revealed targeting BIP was associated with significant improvements of radiation sensitivity. Further analyses revealed that HA15 enhanced radiation-induced endoplasmic reticulum (ER) stress and immunogenic cell death (ICD) in ESCC. Clinical data indicated that high expression of BIP was associated with poor survival in patients of ESCC. In conclusion, proteomics analysis suggested BIP was a promising predictor of radiation response in locally advanced ESCC. The BIP inhibitor HA15 acted as an ER stress inducer and ICD stimulator; RT combined with HA15 was effective in suppressing the growth of ESCC in vitro and in vivo. Pretreatment BIP was an essential prognostic biomarker in locally advanced ESCC patients treated with RT.
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Affiliation(s)
- Hui Luo
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
| | - Liuxiang Wang
- Academy of Medical ScienceZhengzhou UniversityZhengzhouChina
| | - Deju Zhang
- Food and Nutritional SciencesSchool of Biological Sciences, The University of Hong KongHong KongChina
| | - Yanan Sun
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shujuan Wang
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shuai Song
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
| | - Hong Ge
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
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Jeon J, Yoon B, Dey A, Song SH, Li Y, Joo H, Park JH. Self-immolative polymer-based immunogenic cell death inducer for regulation of redox homeostasis. Biomaterials 2023; 295:122064. [PMID: 36827894 DOI: 10.1016/j.biomaterials.2023.122064] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/21/2023]
Abstract
Doxorubicin (DOX), widely used as an anticancer drug, is considered an immunogenic cell death (ICD) inducer that enhances cancer immunotherapy. However, its extended application as an ICD inducer has been limited owing to poor antigenicity and inefficient adjuvanticity. To enhance the immunogenicity of DOX, we prepare a reactive oxygen species (ROS)-responsive self-immolative polymer (R-SIP) that can efficiently destroy redox homeostasis via self-immolation-mediated glutathione depletion in cancer cells. Owing to its amphiphilic nature, R-SIP self-assemble into nano-sized particles under aqueous conditions, and DOX is efficiently encapsulated inside the nanoparticles by a simple dialysis method. Interestingly, when treated with 4T1 cancer cells, DOX-encapsulated R-SIP (DR-SIP) induces the phosphorylation of eukaryotic translation initiation factor 2α and overexpression of ecto-calreticulin, resulting in endoplasmic reticulum-associated ICD. In addition, DR-SIP contributes to the maturation of dendritic cells by promoting the release of damage-associated molecular patterns (DAMPs) from cancer cells. When intravenously administered to tumor-bearing mice, DR-SIP remarkably inhibits tumor growth compared with DOX alone. Overall, DR-SIP may have the potential to elicit an immune response as an ICD inducer.
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Affiliation(s)
- Jueun Jeon
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Been Yoon
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Anup Dey
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Seok Ho Song
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yuce Li
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Hyeyeon Joo
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Republic of Korea; Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea.
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49
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Sen S, Karoscik K, Maier E, Arambula JF. Immunogenic cell death-inducing metal complexes: From the benchtop to the clinic. Curr Opin Chem Biol 2023; 73:102277. [PMID: 36867977 DOI: 10.1016/j.cbpa.2023.102277] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 03/05/2023]
Abstract
The immune system presents a complex array of processes designed to maintain homeostasis in malignant cellular growth. Malignancy is the result of a breakdown in immune surveillance by cancer cells evading immune recognition. Significant efforts have been made in modulating immune checkpoint signaling cascades to bypass the resulting immune evasion and establish an anticancer effect. More recently, it was discovered that a form of regulated cell death can involve the stimulation of immune response as its downstream effect and subsequently re-establish immune surveillance. This mechanism, known as immunogenic cell death (ICD), is being exploited as a target to prevent tumor relapse and prevent cancer metastasis. It is now appreciated that metal-based compounds play a key role in ICD activation due to their unique biochemical properties and interactions within cancer cells. With fewer than 1% of known anticancer agents documented as ICD inducers, recent efforts have been made to identify novel entities capable of stimulating a more potent anticancer immune response. While the recent reviews by us or others focus primarily on either discussing the chemical library of ICD inducers or intricate detailing of biological pathways associated with ICD, this review aims to bridge these two topics as a concise summary. Furthermore, early clinical evidence and future directions of ICD are briefly summarized.
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Affiliation(s)
- Sajal Sen
- Department of Biological Engineering, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, MA 02139, USA.
| | | | - Esther Maier
- Drug Dynamics Institute, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA
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Neo SY, Siew YY, Yew HC, He Y, Poh KL, Tsai YC, Ng SL, Tan WX, Chong TI, Lim CSES, Ho SSW, Singh D, Ali A, Linn YC, Tan CH, Seow SV, Koh HL. Effects of Leea indica leaf extracts and its phytoconstituents on natural killer cell-mediated cytotoxicity in human ovarian cancer. BMC Complement Med Ther 2023; 23:79. [PMID: 36899361 PMCID: PMC10007844 DOI: 10.1186/s12906-023-03904-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/01/2023] [Indexed: 03/12/2023] Open
Abstract
BACKGROUND The rich biodiversity of medicinal plants and their importance as sources of novel therapeutics and lead compounds warrant further research. Despite advances in debulking surgery and chemotherapy, the risks of recurrence of ovarian cancer and resistance to therapy are significant and the clinical outcomes of ovarian cancer remain poor or even incurable. OBJECTIVE This study aims to investigate the effects of leaf extracts from a medicinal plant Leea indica and its selected phytoconstituents on human ovarian cancer cells and in combination with oxaliplatin and natural killer (NK) cells. METHODS Fresh, healthy leaves of L. indica were harvested and extracted in 70% methanol by maceration. The crude extract was partitioned with n-hexane, dichloromethane and ethyl acetate. Selected extracts and compounds were analyzed for their effects on cell viability of human ovarian cancer cells, NK cell cytotoxicity, and stress ligands expression for NK cell receptors. They were also evaluated for their effects on TNF-α and IL-1β production by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated human U937 macrophages. RESULTS Leaf extracts of L. indica increased the susceptibility of human ovarian tumor cells to NK cell-mediated cytotoxicity. Treatment of cancer cells with methyl gallate but not gallic acid upregulated the expression of stress ligands. Tumor cells pretreated with combination of methyl gallate and low concentration of oxaliplatin displayed increased levels of stress ligands expression and concomitantly enhanced susceptibility to NK cell-mediated cytolysis. Further, NK cells completely abrogated the growth of methyl gallate-pretreated ovarian cancer cells. The leaf extracts suppressed TNF-α and IL-1β production in human U937 macrophages. Methyl gallate was more potent than gallic acid in down-regulating these cytokine levels. CONCLUSIONS We demonstrated for the first time that leaf extracts of L. indica and its phytoconstituent methyl gallate enhanced the susceptibility of ovarian tumor cells to NK cell cytolysis. These results suggest that the combined effect of methyl gallate, oxaliplatin and NK cells in ovarian cancer cells warrants further investigation, for example for refractory ovarian cancer. Our work is a step towards better scientific understanding of the traditional anticancer use of L. indica.
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Affiliation(s)
- Soek-Ying Neo
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Yin-Yin Siew
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Hui-Chuing Yew
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Yaqian He
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Keng-Ling Poh
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Yi-Chen Tsai
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Shu-Ling Ng
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Wei-Xun Tan
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Teck-Ian Chong
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Claire Sophie En-Shen Lim
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Samuel Shan-Wei Ho
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Deepika Singh
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
| | - Azhar Ali
- Cancer Science Institute of Singapore, 14 Medical Drive, Singapore, 117599 Singapore
| | - Yeh-Ching Linn
- Department of Haematology, Singapore General Hospital, 20 College Road, Singapore, 169856 Singapore
| | - Chay-Hoon Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600 Singapore
| | - See-Voon Seow
- National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610 Singapore
| | - Hwee-Ling Koh
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543 Singapore
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