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1
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Xu L, Wang S, Li D, Yang B, Zhang J, Ran L, Liu S, Zhang Q, Li B. Dual targeting of ENPP3 and SIRPα with a bispecific antibody enhances macrophage-mediated immunity in renal cell carcinoma. Biochem Biophys Res Commun 2025; 769:151955. [PMID: 40349459 DOI: 10.1016/j.bbrc.2025.151955] [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: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Renal cell carcinoma (RCC) remains a therapeutic challenge despite recent immunotherapy advances. We identified ENPP3 and SIRPα as significantly overexpressed in RCC tissues with positive correlation and prognostic relevance. Based on these findings, we developed a novel bispecific antibody simultaneously targeting tumor-associated ENPP3 and macrophage checkpoint SIRPα. The ENPP3-SIRPα bispecific antibody demonstrated specific binding to both targets and effectively blocked CD47-SIRPα interaction in vitro. In vivo this bispecific approach exhibited superior anti-tumor efficacy compared to monotherapies or their combination as separate agents. Mechanistic studies confirmed that the therapeutic effect was macrophage-dependent, with enhanced phagocytosis of tumor cells. Importantly, the bispecific antibody maintained a favorable safety profile with no significant hematological abnormalities observed during treatment. These findings demonstrate that simultaneous targeting of ENPP3 and SIRPα represents a promising immunotherapeutic strategy for RCC, combining tumor-specific targeting with immune checkpoint inhibition while mitigating potential toxicities associated with systemic SIRPα blockade.
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MESH Headings
- Carcinoma, Renal Cell/immunology
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/therapy
- Kidney Neoplasms/immunology
- Kidney Neoplasms/pathology
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/therapy
- Humans
- Receptors, Immunologic/immunology
- Receptors, Immunologic/antagonists & inhibitors
- Receptors, Immunologic/metabolism
- Macrophages/immunology
- Macrophages/drug effects
- Animals
- Antibodies, Bispecific/immunology
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/pharmacology
- Cell Line, Tumor
- Antigens, Differentiation/immunology
- Antigens, Differentiation/metabolism
- Mice
- Immunotherapy
- Phagocytosis/drug effects
- Female
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Affiliation(s)
- Lijun Xu
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Shanlong Wang
- The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China
| | - Dan Li
- General Psychiatric Department, Henan Rongkang Hospital, Luoyang, Henan, China
| | - Bowen Yang
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Junhan Zhang
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Longchao Ran
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Shujian Liu
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Qi Zhang
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Bingyu Li
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China; The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China.
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2
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Yang J, Li X, Li T, Mei J, Chen Y. Recent advances in biomimetic nanodelivery systems for cancer Immunotherapy. Mater Today Bio 2025; 32:101726. [PMID: 40270890 PMCID: PMC12017925 DOI: 10.1016/j.mtbio.2025.101726] [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: 12/25/2024] [Revised: 02/26/2025] [Accepted: 04/01/2025] [Indexed: 04/25/2025] Open
Abstract
Tumor immunotherapy is a developing and promising therapeutic method. However, the mechanism of tumor immune microenvironment and individual differences of patients make the clinical application of immunotherapy still very limited. The resulting targeting of the tumor environment and immune system is a suitable strategy for tumor therapy. Biomimetic nanodelivery systems (BNDS) coated with nanoparticles has brought new hope for tumor immunotherapy. Due to its high targeting, maximum drug delivery efficiency and immune escape, BNDS has become one of the options for tumor immunotherapy in the future. BNDS combines the advantages of natural cell membranes and nanoparticles and has good targeting properties. This review summarizes the relationship between tumor and immune microenvironment, classification of immunotherapy, engineering modification of cell membrane, and a comprehensive overview of different types of membrane BNDS in immunotherapy. Furthermore, the prospects and challenges of biomimetic nanoparticles coated with membranes in tumor immunotherapy are further discussed.
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Affiliation(s)
- Jiawei Yang
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China, No. 508 North Second Ring East Road, Ningbo, 315302, Zhejiang, China
| | - Xueqi Li
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China, No. 508 North Second Ring East Road, Ningbo, 315302, Zhejiang, China
| | - Tongyu Li
- Department of Hematology, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, China
| | - Jin Mei
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China, No. 508 North Second Ring East Road, Ningbo, 315302, Zhejiang, China
- Institute of Engineering Medicine, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, China
| | - Ying Chen
- Institute of Engineering Medicine, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, China
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3
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Liu S, He X, Liang S, Wu A, Liu L, Hu W. Carbon ion irradiation mobilizes antitumor immunity: from concept to the clinic. Radiat Oncol 2025; 20:85. [PMID: 40405246 PMCID: PMC12100795 DOI: 10.1186/s13014-025-02647-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 04/23/2025] [Indexed: 05/24/2025] Open
Abstract
Carbon ion radiotherapy (CIRT), a type of particle therapy, is at the forefront of clinical oncology treatments due to its superior physical properties and biological performance. Although CIRT has demonstrated outstanding therapeutic outcomes in clinical settings, the biological mechanisms underpinning its effects, particularly its immunogenic potential and the superiority of its induced antitumor immune response compared to photon radiotherapy, remain areas of active investigation. This review summarizes the latest research progress on the mechanisms of antitumor immune responses triggered by CIRT and discusses preclinical and clinical studies related to combined CIRT and immunotherapy (CCIT). Against the backdrop of extensive research and significant clinical efficacy achieved by combining radiotherapy with immunotherapy, this review provides a theoretical foundation for a better understanding of the superior tumor cell-killing effects of CIRT and the underlying immunological mechanisms. Further insights into the factors affecting the efficacy, toxic effects, and developmental limitations of this combination therapy mode will be instrumental in guiding the conduction of CCIT studies.
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Affiliation(s)
- Shanghai Liu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, China
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiangyang He
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, China
| | - Siqi Liang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, China
| | - Anqing Wu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, China.
| | - Lu Liu
- Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, China.
| | - Wentao Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, China.
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4
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Xu L, Yang B, Zhang J, Liu S, Zhang Q, Ran L, Li B. Targeting ALPPL2 with a novel CD89 bispecific antibody reprograms macrophages to enhance anti-tumor immunity. Biochem Biophys Res Commun 2025; 762:151761. [PMID: 40209501 DOI: 10.1016/j.bbrc.2025.151761] [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: 04/02/2025] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 04/12/2025]
Abstract
Immunotherapy holds promise for cancer treatment, but its efficacy in solid tumors is often limited by the immunosuppressive tumor microenvironment (TME). Macrophages, abundant within the TME, can be reprogrammed to elicit anti-tumor immunity. We developed a novel bispecific antibody, ALPPL2-CD89, to specifically target and activate macrophages within the tumor. The ALPPL2-CD89 bispecific antibody demonstrated high binding affinity to both targets and significantly enhanced macrophage-mediated phagocytosis of tumor cells. In vivo studies using human CD89 transgenic mice bearing ALPPL2-expressing tumors showed significant tumor growth inhibition. Analysis of the tumor microenvironment revealed that ALPPL2-CD89 treatment increased CD3+ and CD8+ T cell infiltration, and shifted tumor-associated macrophages toward a pro-inflammatory M1 phenotype. Our findings establish ALPPL2-CD89 as a promising therapeutic candidate that effectively reprograms the myeloid compartment to drive potent anti-tumor immunity against ALPPL2-positive malignancies.
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Affiliation(s)
- Lijun Xu
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Bowen Yang
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Junhan Zhang
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Shujian Liu
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Qi Zhang
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Longchao Ran
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China
| | - Bingyu Li
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China; The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China.
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5
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Ying S, Liu H, Zhang Y, Mei Y. Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies. Vaccines (Basel) 2025; 13:496. [PMID: 40432108 PMCID: PMC12115466 DOI: 10.3390/vaccines13050496] [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: 03/21/2025] [Revised: 04/29/2025] [Accepted: 05/01/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival.
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Affiliation(s)
- Shiding Ying
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Haiyan Liu
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yu Mei
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
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6
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Pascoal LB, Jalalizadeh M, Barbosa G, da Silva ANMR, Queiroz MAF, Laukhtina E, Shariat SF, Gambero A, Reis LO. Viral infections and immune modulation in bladder cancer: implications for immunotherapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002311. [PMID: 40291982 PMCID: PMC12022759 DOI: 10.37349/etat.2025.1002311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/27/2025] [Indexed: 04/30/2025] Open
Abstract
This review explores the intricate relationship between viral infections and Bacillus Calmette-Guerin (BCG) efficacy, emphasizing immune modulation mechanisms that may influence treatment outcomes. Since its introduction in 1976, intravesical BCG has been a cornerstone in managing non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumors (TURBT). Despite its success, variability in response rates suggests that host immune status, influenced by persistent infections, immunosenescence, and antigenic overload, may play a crucial role in therapeutic effectiveness. Chronic viral infections can modulate T cell responses, leading to immune exhaustion and impaired antitumor immunity. This review discusses the interplay between viral antigenic load, immune dysfunction, and tumor microenvironment remodeling, highlighting their potential impact on immunotherapies. By integrating insights from virome analysis, immune profiling, and tumor characterization, this review proposes personalized strategies to enhance immunotherapy efficacy. A deeper understanding of viral-induced immune dysregulation may improve prognostic assessment, optimize treatment protocols, and reduce healthcare costs associated with bladder cancer. Future research should focus on targeted interventions to mitigate the immunosuppressive effects of chronic infections, ultimately improving patient outcomes in NMIBC management.
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Affiliation(s)
- Lívia Bitencourt Pascoal
- UroScience, State University of Campinas, Campinas 13083-970, Brazil
- ImmunOncology, Pontifical Catholic University of Campinas, Campinas 13060-904, Brazil
- INCT UroGen, National Institute of Science, Technology and Innovation in Genitourinary Cancer (INCT), Campinas 13087-571, Brazil
| | | | - Gabriela Barbosa
- UroScience, State University of Campinas, Campinas 13083-970, Brazil
- ImmunOncology, Pontifical Catholic University of Campinas, Campinas 13060-904, Brazil
- INCT UroGen, National Institute of Science, Technology and Innovation in Genitourinary Cancer (INCT), Campinas 13087-571, Brazil
| | | | - Maria Alice Freitas Queiroz
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil
| | - Ekaterina Laukhtina
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Shahrokh F. Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
- Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman 19328, Jordan
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Urology, Weill Cornell Medical College, New York, NY 10065, USA
| | - Alessandra Gambero
- ImmunOncology, Pontifical Catholic University of Campinas, Campinas 13060-904, Brazil
- INCT UroGen, National Institute of Science, Technology and Innovation in Genitourinary Cancer (INCT), Campinas 13087-571, Brazil
| | - Leonardo O. Reis
- UroScience, State University of Campinas, Campinas 13083-970, Brazil
- ImmunOncology, Pontifical Catholic University of Campinas, Campinas 13060-904, Brazil
- INCT UroGen, National Institute of Science, Technology and Innovation in Genitourinary Cancer (INCT), Campinas 13087-571, Brazil
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Bayat M, Nahand JS. Battlegrounds of treatment resistance: decoding the tumor microenvironment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04055-5. [PMID: 40131387 DOI: 10.1007/s00210-025-04055-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
The tumor microenvironment (TME) emerges as a formidable actor in the cancer treatment landscape, wielding the power to thwart therapeutic efficacy across various modalities, including chemotherapy, radiotherapy, immunotherapy, targeted therapy, and hormonal therapy. This intricate ecosystem comprising diverse cellular constituents, signaling molecules, and the extracellular matrix fosters a dynamic interplay that profoundly influences tumor behavior and treatment outcomes. This review explores the mechanisms through which the TME drives resistance to standard therapies, emphasizing key factors such as hypoxia, immune evasion, and metabolic reprogramming. Furthermore, we illuminate innovative strategies aimed at reprogramming this hostile environment, including the application of therapeutic vaccines, CAR T cell therapy, and combination immunotherapies designed to enhance anti-tumor responses. By advocating for multidimensional approaches that dismantle the TME's barriers to effective treatment, this review calls for a transformative shift in cancer treatment paradigms. By bridging the gap between the TME's complexities and targeted therapeutic strategies, we pave the way for targeted interventions that promise to enhance clinical outcomes and improve patient prognosis in the relentless battle against cancer.
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Affiliation(s)
- Mobina Bayat
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Mao L, Ma Y, Wen X, Luo Z, Zhu H, Kong J, Liu S, Fan X, Wang J, He C, Wu YL. Iron-glucose oxidase nanogel assembly for amplified starvation-ferroptosis anti-tumor therapy. Int J Biol Macromol 2025; 289:138804. [PMID: 39689793 DOI: 10.1016/j.ijbiomac.2024.138804] [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: 08/15/2024] [Revised: 12/14/2024] [Accepted: 12/14/2024] [Indexed: 12/19/2024]
Abstract
Developing advanced and effective enzyme-drug systems for cancer treatment is of significant interest. Herein, a novel approach is reported to create a highly active and robust enzyme-drug system. Glucose oxidase nanogels (nGOx) are first synthesized by polymerization on the surface of GOx using vinylimidazole as comonomers. Fe3+ are utilized to induce self-assembly of nGOx through the imidazole-metal coordination interaction to form GOx nanogel clusters (Fe@nGOx), enhancing the permeability and retention of nGOx into tumor cells by EPR effect. nGOx can deplete glucose in the presence of oxygen and generate H2O2, which is converted to highly cytotoxic hydroxyl radical (·OH) by Fe3+ and GSH, and the proximity between Fe3+ and GOx act in tandem for enhanced tumor therapy. The FeIII/FeII redox cycle reacts with GSH and H2O2, enabling continuous generation of ·OH within tumor cells, thus facilitating the anticancer effect. Moreover, the generation of H2O2 and ·OH can further promote the repolarization of tumor-associated macrophages from an M2 phenotype towards an M1 phenotype polarization, thus enhancing immune response. The cascade reaction between GOx and Fe3+/Fe2+ endows Fe@nGOx with excellent anti-tumor efficacy in mice models, highlighting its potential as a promising anticancer drug for clinical applications. This work establishes a new platform for utilizing enzyme/protein and metal ion complexes in versatile applications, advancing the field of enzyme-based cancer therapies.
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Affiliation(s)
- Liuzhou Mao
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, PR China
| | - Yedong Ma
- Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Republic of Singapore
| | - Xiaoqing Wen
- Drug clinical trial institution, The first affiliated hospital of Xiamen university, Xiamen, Fujian, PR China
| | - Zheng Luo
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, PR China
| | - Houjuan Zhu
- Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology, and Research (A∗STAR), 2 Fusionopolis Way, Innovis, Singapore 138634, Republic of Singapore
| | - Junhua Kong
- Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology, and Research (A∗STAR), 2 Fusionopolis Way, Innovis, Singapore 138634, Republic of Singapore
| | - Siqi Liu
- Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Republic of Singapore
| | - Xiaotong Fan
- Institute of Sustainability for Chemicals, Energy and Environment (ISCE2), Agency for Science, Technology and Research (A*STAR), 1 Pesek Road, Jurong Island, Singapore 627833, Republic of Singapore.
| | - Jinling Wang
- Department of Emergency and Critical Care Center, The Second Affiliated Hospital of Guangdong Medical University, No. 12 Minyou Road, Xiashan, Zhanjiang, Guangdong 524003, PR China.
| | - Chaobin He
- Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Republic of Singapore; Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology, and Research (A∗STAR), 2 Fusionopolis Way, Innovis, Singapore 138634, Republic of Singapore.
| | - Yun-Long Wu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, PR China.
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Mwale PF, Hsieh CT, Yen TL, Jan JS, Taliyan R, Yang CH, Yang WB. Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications. Mol Neurodegener 2025; 20:7. [PMID: 39827337 PMCID: PMC11742494 DOI: 10.1186/s13024-025-00801-8] [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: 09/24/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025] Open
Abstract
Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood-brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.
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Affiliation(s)
- Pharaoh Fellow Mwale
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei, 110, Taiwan
| | - Cheng-Ta Hsieh
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei, 110, Taiwan
- Division of Neurosurgery, Department of Surgery, Cathay General Hospital, Taipei City, 106438, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan
- Department of Medicine, School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan
| | - Ting-Lin Yen
- Department of Medical Research, Cathay General Hospital, Taipei, 22174, Taiwan
| | - Jing-Shiun Jan
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei, 110, Taiwan
| | - Rajeev Taliyan
- Neuropsychopharmacology Division, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani, Rajasthan, India
| | - Chih-Hao Yang
- Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei, 110, Taiwan.
- Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan.
| | - Wen-Bin Yang
- Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan.
- Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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10
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Ahmad I, Altameemi KKA, Hani MM, Ali AM, Shareef HK, Hassan ZF, Alubiady MHS, Al-Abdeen SHZ, Shakier HG, Redhee AH. Shifting cold to hot tumors by nanoparticle-loaded drugs and products. Clin Transl Oncol 2025; 27:42-69. [PMID: 38922537 DOI: 10.1007/s12094-024-03577-3] [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: 05/28/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024]
Abstract
Cold tumors lack antitumor immunity and are resistant to therapy, representing a major challenge in cancer medicine. Because of the immunosuppressive spirit of the tumor microenvironment (TME), this form of tumor has a low response to immunotherapy, radiotherapy, and also chemotherapy. Cold tumors have low infiltration of immune cells and a high expression of co-inhibitory molecules, such as immune checkpoints and immunosuppressive molecules. Therefore, targeting TME and remodeling immunity in cold tumors can improve the chance of tumor repression after therapy. However, tumor stroma prevents the infiltration of inflammatory cells and hinders the penetration of diverse molecules and drugs. Nanoparticles are an intriguing tool for the delivery of immune modulatory agents and shifting cold to hot tumors. In this review article, we discuss the mechanisms underlying the ability of nanoparticles loaded with different drugs and products to modulate TME and enhance immune cell infiltration. We also focus on newest progresses in the design and development of nanoparticle-based strategies for changing cold to hot tumors. These include the use of nanoparticles for targeted delivery of immunomodulatory agents, such as cytokines, small molecules, and checkpoint inhibitors, and for co-delivery of chemotherapy drugs and immunomodulatory agents. Furthermore, we discuss the potential of nanoparticles for enhancing the efficacy of cancer vaccines and cell therapy for overcoming resistance to treatment.
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Affiliation(s)
- Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | | | - Mohaned Mohammed Hani
- Department of Medical Instrumentation Engineering Techniques, Imam Ja'afar Al-Sadiq University, Al Muthanna, Iraq
| | - Afaq Mahdi Ali
- Department of Pharmaceutics, Al-Turath University College, Baghdad, Iraq
| | - Hasanain Khaleel Shareef
- Department of Medical Biotechnology, College of Science, Al-Mustaqbal University, Hilla, Iraq
- Biology Department, College of Science for Women, University of Babylon, Hilla, Iraq
| | | | | | | | | | - Ahmed Huseen Redhee
- Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
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11
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Mussa A, Ismail NH, Hamid M, Al-Hatamleh MAI, Bragoli A, Hajissa K, Mokhtar NF, Mohamud R, Uskoković V, Hassan R. Understanding the role of TNFR2 signaling in the tumor microenvironment of breast cancer. J Exp Clin Cancer Res 2024; 43:312. [PMID: 39609700 PMCID: PMC11603874 DOI: 10.1186/s13046-024-03218-1] [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: 08/21/2024] [Accepted: 10/29/2024] [Indexed: 11/30/2024] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed malignancy among women. It is characterized by a high level of heterogeneity that emerges from the interaction of several cellular and soluble components in the tumor microenvironment (TME), such as cytokines, tumor cells and tumor-associated immune cells. Tumor necrosis factor (TNF) receptor 2 (TNFR2) appears to play a significant role in microenvironmental regulation, tumor progression, immune evasion, drug resistance, and metastasis of many types of cancer, including BC. However, the significance of TNFR2 in BC biology is not fully understood. This review provides an overview of TNFR2 biology, detailing its activation and its interactions with important signaling pathways in the TME (e.g., NF-κB, MAPK, and PI3K/Akt pathways). We discuss potential therapeutic strategies targeting TNFR2, with the aim of enhancing the antitumor immune response to BC. This review provides insights into role of TNFR2 as a major immune checkpoint for the future treatment of patients with BC.
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Affiliation(s)
- Ali Mussa
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia
- Department of Biology, Faculty of Education, Omdurman Islamic University, P.O. Box 382, Omdurman, Sudan
| | - Nor Hayati Ismail
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia
| | - Mahasin Hamid
- Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Hunan Province, Changsha, 410013, China
- Department of Zoology, Faculty of Sciences and Information Technology, University of Nyala, Nyala, 63311, Sudan
| | - Mohammad A I Al-Hatamleh
- Division of Hematology and Oncology, Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Anthony Bragoli
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Khalid Hajissa
- Department of Zoology, Faculty of Science and Technology, Omdurman Islamic University, P.O. Box 382, Omdurman, Sudan
| | - Noor Fatmawati Mokhtar
- Institute for Research in Molecular Medicine (iNFORMM), Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia.
| | - Vuk Uskoković
- TardigradeNano LLC, Irvine, CA, 92604, USA
- Division of Natural Sciences, Fullerton College, Fullerton, CA, 92832, USA
| | - Rosline Hassan
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu , Kelantan, 16150, Malaysia.
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12
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Tao Y, Du M, Zhu M, Wang Y, Fei Y, Zhao YQ, Ma J, Fan R, Dai F, Chen J, Yin J, Fan B, Zeng G. Antitumor Effect of Peptide-Camptothecin Conjugate Targeting CD133 Protein. Bioconjug Chem 2024; 35:1859-1869. [PMID: 39527780 DOI: 10.1021/acs.bioconjchem.4c00485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The peptide-drug conjugate (PDC) has emerged as one of the new approaches for cancer therapy, which has the advantages of improved drug target ability and reduced adverse effects compared with the traditional chemotherapy. CD133 is a surface antigen specific to cancer stem cells, which are thought to be responsible for the self-renewal, proliferation, metastasis, and chemoresistance of cancer cells. A PDC for CD133 was designed by us, and it consists of CD133 targeting peptide LS-7 (amino acid sequence LQNAPRS), a pH-sensitive linker (succinyl), and a cytotoxic payload, the cytotoxic molecule camptothecin (CPT) with potent toxicity in vivo and in vitro. An antitumor study exhibited that the conjugate LS-7-CPT has not only improved its cytotoxicity in tumor cells but also retained its anticancer effect in vivo. In addition, the acute toxicity in mice of LS-7-CPT has been improved and the maximum tolerated dose has been increased by at least 56.2-fold. Pull-down and in vivo fluorescent imaging results indicated that LS-7-CPT was enriched in mice tumors by targeting CD133 protein. As far as we know, this is the first report for a PDC molecule designed for CD133, which is important for the study of CPT drug development.
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Affiliation(s)
- Yang Tao
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Maoxin Du
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Meihua Zhu
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Yinyue Wang
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Yusong Fei
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
| | - Yu-Qiang Zhao
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
| | - Junjie Ma
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Ruifeng Fan
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Fang Dai
- School of Chemistry and Environmental Engineering, Qujing Normal University, Qujing 655011, China
| | - Jingchao Chen
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Junlin Yin
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Baomin Fan
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Guangzhi Zeng
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
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13
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Zhu E, Xie Q, Huang X, Zhang Z. Application of spatial omics in gastric cancer. Pathol Res Pract 2024; 262:155503. [PMID: 39128411 DOI: 10.1016/j.prp.2024.155503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024]
Abstract
Gastric cancer (GC), a globally prevalent and lethal malignancy, continues to be a key research focus. However, due to its considerable heterogeneity and complex pathogenesis, the treatment and diagnosis of gastric cancer still face significant challenges. With the rapid development of spatial omics technology, which provides insights into the spatial information within tumor tissues, it has emerged as a significant tool in gastric cancer research. This technology affords new insights into the pathology and molecular biology of gastric cancer for scientists. This review discusses recent advances in spatial omics technology for gastric cancer research, highlighting its applications in the tumor microenvironment (TME), tumor heterogeneity, tumor genesis and development mechanisms, and the identification of potential biomarkers and therapeutic targets. Moreover, this article highlights spatial omics' potential in precision medicine and summarizes existing challenges and future directions. It anticipates spatial omics' continuing impact on gastric cancer research, aiming to improve diagnostic and therapeutic approaches for patients. With this review, we aim to offer a comprehensive overview to scientists and clinicians in gastric cancer research, motivating further exploration and utilization of spatial omics technology. Our goal is to improve patient outcomes, including survival rates and quality of life.
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Affiliation(s)
- Erran Zhu
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Qi Xie
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Xinqi Huang
- Excellent Class, Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiwei Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology of Hunan; Department of Pathology, Department of Pathology of Hengyang Medical College, University of South China; The First Affiliated Hospital of University of South China, China.
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14
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Yoel A, Adjumain S, Liang Y, Daniel P, Firestein R, Tsui V. Emerging and Biological Concepts in Pediatric High-Grade Gliomas. Cells 2024; 13:1492. [PMID: 39273062 PMCID: PMC11394548 DOI: 10.3390/cells13171492] [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: 06/27/2024] [Revised: 08/09/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors.
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Affiliation(s)
- Abigail Yoel
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; (A.Y.); (S.A.); (Y.L.); (P.D.); (R.F.)
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Shazia Adjumain
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; (A.Y.); (S.A.); (Y.L.); (P.D.); (R.F.)
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Yuqing Liang
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; (A.Y.); (S.A.); (Y.L.); (P.D.); (R.F.)
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Paul Daniel
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; (A.Y.); (S.A.); (Y.L.); (P.D.); (R.F.)
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Ron Firestein
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; (A.Y.); (S.A.); (Y.L.); (P.D.); (R.F.)
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
| | - Vanessa Tsui
- Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; (A.Y.); (S.A.); (Y.L.); (P.D.); (R.F.)
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia
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15
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Peng X, He Z, Yuan D, Liu Z, Rong P. Lactic acid: The culprit behind the immunosuppressive microenvironment in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189164. [PMID: 39096976 DOI: 10.1016/j.bbcan.2024.189164] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 07/25/2024] [Accepted: 07/28/2024] [Indexed: 08/05/2024]
Abstract
As a solid tumor with high glycolytic activity, hepatocellular carcinoma (HCC) produces excess lactic acid and increases extracellular acidity, thus forming a unique immunosuppressive microenvironment. L-lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) play a very important role in glycolysis. LDH is the key enzyme for lactic acid (LA) production, and MCT is responsible for the cellular import and export of LA. The synergistic effect of the two promotes the formation of an extracellular acidic microenvironment. In the acidic microenvironment of HCC, LA can not only promote the proliferation, survival, transport and angiogenesis of tumor cells but also have a strong impact on immune cells, ultimately leading to an inhibitory immune microenvironment. This article reviews the role of LA in HCC, especially its effect on immune cells, summarizes the progress of LDH and MCT-related drugs, and highlights the potential of immunotherapy targeting lactate combined with HCC.
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Affiliation(s)
- Xiaopei Peng
- Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, China
| | - Zhenhu He
- Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, China
| | - Dandan Yuan
- Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, China
| | - Zhenguo Liu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Pengfei Rong
- Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, China.
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16
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Li X, Sun X, Chen H, Wang Y, Chen H, Gao Y. Boron Dipyrromethene-Based Nanotheranostic System for Sonophotoassisted Therapy and Simultaneous Monitoring of Tumor Immune Microenvironment Reprogramming. ACS NANO 2024; 18:18230-18245. [PMID: 38950337 DOI: 10.1021/acsnano.4c00650] [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: 07/03/2024]
Abstract
Therapy-induced modulation of the tumor microenvironment (TME) to overcome the immunosuppressive TME is considered to be an opportunity for cancer treatment. However, monitoring of TME modulation during the therapeutic process to accurately determine immune responses and adjust treatment plans in a timely manner remains to be challenging. Herein, we report a carrier-free nanotheranostic system (CANPs) assembled by two boron dipyrromethene (BODIPY) dyes, a sonophotosensitizer C-BDP, and a nitric oxide (NO) probe amino-BODIPY (A-BDP). CANPs can exert combined sonophototherapeutic effects of C-BDP under ultrasound and light irradiation and simultaneously induce inflammatory TME, as well as emit bright fluorescence via A-BDP by monitoring tumor-associated macrophages (TAMs) repolarization through the released NO in vitro and in vivo. Of note, transforming growth factor-β (TGF-β) could be the key cytokine involved in the sonophototherapy-induced TME reprogramming. By virtue of high physiological stability, good biocompatibility, and effective tumor targetability, CANPs could be a potential nanotheranostic system for the simultaneous induction and detection of TME reprogramming triggered by sonophototherapy.
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Affiliation(s)
- Xudong Li
- Cancer Metastasis Alert and Prevention Center, College of Chemistry, and Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China
| | - Xianbin Sun
- Cancer Metastasis Alert and Prevention Center, College of Chemistry, and Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China
| | - Hui Chen
- College of Chemistry, Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), Fuzhou University, Fuzhou, Fujian 350116, China
| | - Ya Wang
- Cancer Metastasis Alert and Prevention Center, College of Chemistry, and Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China
| | - Haijun Chen
- College of Chemistry, Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), Fuzhou University, Fuzhou, Fujian 350116, China
| | - Yu Gao
- Cancer Metastasis Alert and Prevention Center, College of Chemistry, and Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350108, China
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17
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do Nascimento RG, da Conceição MPF, de Bastos DR, de Toledo Osorio CAB, López RVM, Reis EM, Cerqueira OLD. Prognostic value of Maspin protein level in patients with triple negative breast cancer. Sci Rep 2024; 14:15982. [PMID: 38987610 PMCID: PMC11237076 DOI: 10.1038/s41598-024-53870-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/06/2024] [Indexed: 07/12/2024] Open
Abstract
The search for prognostic markers in breast cancer has bumped into a typical feature of these tumors, intra and intertumoral heterogeneity. Changes in the expression profile, localization of these proteins or shedding to the surrounding stroma can be useful in the search for new markers. In this context, classification by molecular subtypes can bring perspectives for both diagnosis and screening for appropriate treatments. However, the Triple Negative (TN) subtype, which is already the one with the worst prognosis, lacks appropriate and consistent molecular markers. In this work, we analyzed 346 human breast cancer samples in tissue microarrays (TMA) from cases diagnosed with invasive breast carcinoma to assess the expression and localization pattern of Maspin and their correlation with clinical parameters. To complement our findings, we also used TCGA data to analyze the mRNA levels of these respective genes. Our data suggests that the TN subtype demonstrates a higher level of cytoplasmic Maspin compared to the other subtypes. Maspin transcript levels follow the same trend. However, TN patients with lower Maspin expression tend to have worse overall survival and free-survival metastasis rates. Finally, we used Maspin expression data to verify possible relationships with the clinicopathological information of our cohort. Our univariate analyses indicate that Maspin is related to the expression of estrogen receptor (ER) and progesterone receptor (PR). Furthermore, Maspin expression levels also showed correlation with Scarff-Bloom-Richardson (SBR) parameter, and stromal Maspin showed a relationship with lymph node involvement. Our data is not consistently robust enough to categorize Maspin as a prognostic marker. However, it does indicate a change in the expression profile within the TN subtype.
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Affiliation(s)
- Renan Gomes do Nascimento
- Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), Clinical Hospital Faculty of Medicine, University of São Paulo (HCFMUSP), São Paulo, SP, 01246-000, Brazil
- Department of Clinical Pharmacy and Oncology, Hospital São Camilo (HSC), São Paulo, SP, 02401-300, Brazil
| | - Mércia Patrícia Ferreira da Conceição
- Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), Clinical Hospital Faculty of Medicine, University of São Paulo (HCFMUSP), São Paulo, SP, 01246-000, Brazil
| | - Daniel Rodrigues de Bastos
- Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), Clinical Hospital Faculty of Medicine, University of São Paulo (HCFMUSP), São Paulo, SP, 01246-000, Brazil
| | | | - Rossana Verónica Mendoza López
- Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), Clinical Hospital Faculty of Medicine, University of São Paulo (HCFMUSP), São Paulo, SP, 01246-000, Brazil
| | - Eduardo Moraes Reis
- Departmento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil
| | - Otto Luiz Dutra Cerqueira
- Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), Clinical Hospital Faculty of Medicine, University of São Paulo (HCFMUSP), São Paulo, SP, 01246-000, Brazil.
- Departmento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.
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18
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Zhang M, Wang S, He M, Zhang Z, Wu J, Sun H, Zhang H, Yang H. Multidimensional analysis of TMEM132A in pan-cancer: unveiling its potential as a biomarker for treatment response prediction. J Cancer 2024; 15:4386-4405. [PMID: 38947398 PMCID: PMC11212083 DOI: 10.7150/jca.96396] [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: 03/19/2024] [Accepted: 05/20/2024] [Indexed: 07/02/2024] Open
Abstract
Background: TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have investigated the involvement of TMEM132A in specific cancers, further systematic studies are required to elucidate its specific mechanisms of action in different cancer types. Methods: We investigated the pan-cancer role of TMEM132A using several databases. We analyzed TMEM132A expression and its correlation with clinical survival, immune checkpoints, tumor stemness score, prognostic value, immunomodulators, genomic profiles, immunological characteristics, immunotherapy and functional enrichment. Results: First, it was observed that TMEM132A expression levels were higher in the majority of tumors compared to non-tumor tissues. In addition, high TMEM132A expression may have a higher prognostic value in some cancers. Furthermore, TMEM132A was significantly associated with immune checkpoints, immunomodulators, prognosis, immunomodulatory genes, tumor stemness score, cell function status and immune infiltration in most tumors. Further analysis of TMEM132A-related gene enrichment, mutation sites and types, RNA modification and genomic heterogeneity showed that the major mutations of TMEM132A were missense mutations and that TMEM132A plays a very important role in UCEC, LUAD and LIHC. Finally, these results suggest that high TMEM132A expression may be associated with a better response to specific immunotherapies. Conclusion: This comprehensive study uncovers an important function for TMEM132A in different types of cancer. It also has the potential to identify TMEM132A as a potential biomarker for predicting treatment response. This may help us to better understand how TMEM132A plays a role in cancer and provide valuable insights for developing personalised treatments.
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Affiliation(s)
- Mingyue Zhang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
| | - Shengli Wang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
| | - Meihong He
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
| | - Zhanpeng Zhang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Jie Wu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
| | - Hongyan Sun
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
| | - Hua Zhang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Hengwen Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, China
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, China
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El-Tanani M, Rabbani SA, Babiker R, Rangraze I, Kapre S, Palakurthi SS, Alnuqaydan AM, Aljabali AA, Rizzo M, El-Tanani Y, Tambuwala MM. Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies. Cancer Lett 2024; 591:216894. [PMID: 38626856 DOI: 10.1016/j.canlet.2024.216894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/29/2024] [Accepted: 04/11/2024] [Indexed: 05/03/2024]
Abstract
This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. The TME, a dynamic ecosystem comprising diverse cellular and acellular elements, not only fosters tumor progression but also profoundly affects the efficacy of conventional and emerging cancer therapies. Through nuanced exploration, this review illuminates the multifaceted nature of the TME, elucidating its capacity to engender drug resistance via mechanisms such as hypoxia, immune evasion, and the establishment of physical barriers to drug delivery. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Furthermore, this review critically evaluates the challenges posed by the complexity and heterogeneity of the TME, which contribute to variable therapeutic responses and potentially unintended consequences. This underscores the need to identify robust biomarkers and advance predictive models to anticipate treatment outcomes, as well as advocate for combination therapies that address multiple facets of the TME. Finally, the review emphasizes the necessity of an interdisciplinary approach and the integration of cutting-edge technologies to unravel the intricacies of the TME, thereby facilitating the development of more effective, adaptable, and personalized cancer treatments. By providing critical insights into the current state of TME research and its implications for the future of oncology, this review highlights the dynamic and evolving landscape of this field.
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Affiliation(s)
- Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
| | - Syed Arman Rabbani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Rasha Babiker
- Physiology Department, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras-al-Khaimah, United Arab Emirates
| | - Imran Rangraze
- Internal Medicine Department, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras-al-Khaimah, United Arab Emirates
| | - Sumedha Kapre
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, Kingsville, TX, 78363, USA
| | - Sushesh Srivastsa Palakurthi
- Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M University, Kingsville, TX, 78363, USA
| | - Abdullah M Alnuqaydan
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
| | - Alaa A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, 21163, Jordan
| | - Manfredi Rizzo
- (D)epartment of Health Promotion, Mother and Childcare, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, Palermo, Italy
| | - Yahia El-Tanani
- Medical School, St George's University of London, Cranmer Terrace, Tooting, London, SW17 0RE, UK.
| | - Murtaza M Tambuwala
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates; Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln, LN6 7TS, UK.
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20
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Zabeti Touchaei A, Vahidi S, Samadani AA. Immune landscape in APC and TP53 related tumor microenvironment in colon adenocarcinoma: A bioinformatic analysis. Eur J Microbiol Immunol (Bp) 2024; 14:154-165. [PMID: 38470482 PMCID: PMC11097784 DOI: 10.1556/1886.2024.00015] [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: 02/02/2024] [Accepted: 02/22/2024] [Indexed: 03/13/2024] Open
Abstract
Introduction APC and TP53 are the two most regularly mutated genes in colon adenocarcinoma (COAD), especially in progressive malignancies and antitumoral immune response. The current bioinformatics analysis investigates the APC and TP53 gene expression profile in colon adenocarcinoma as a prognostic characteristic for survival, particularly concentrating on the correlated immune microenvironment. Methods Clinical and genetic data of colon cancer and normal tissue samples were obtained from The Cancer Genome Atlas (TCGA)-COAD and Genotype-Tissue Expression (GTEx) online databases, respectively. The genetic differential expressions were analyzed in both groups via the one-way ANOVA test. Kaplan-Meier survival curves were applied to estimate the overall survival (OS). P < 0.05 was fixed as statistically significant. On Tumor Immune Estimation Resource and Gene Expression Profiling Interactive Analysis databases, the linkage between immune cell recruitment and APC and TP53 status was assessed through Spearman's correlation analysis. Results APC and TP53 were found mutated in 66.74% and 85.71% of the 454 and 7 TCGA-COAD patients in colon and rectosigmoid junction primary sites, respectively with a higher log2-transcriptome per million reads compared to the GTEx group (318 samples in sigmoid and 368 samples in transverse). Survival curves revealed a worse significant OS for the high-APC and TP53 profile colon. Spearman's analysis of immune cells demonstrated a strong positive correlation between the APC status and infiltration of T cell CD4+, T cell CD8+, NK cell, and macrophages and also a positive correlation between status and infiltration of T cell CD4+, T cell CD8+. Conclusions APC and TP53 gene mutations prevail in colon cancer and are extremely associated with poor prognosis and shortest survival. The infiltrating T cell CD4+, T cell CD8+, NK cell, and macrophages populate the colon microenvironment and regulate the mechanisms of tumor advancement, immune evasion, and sensitivity to standard chemotherapy. More comprehensive research is needed to demonstrate these results and turn them into new therapeutic outlooks.
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Affiliation(s)
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
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21
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Zheng J, Hao H. The importance of cancer-associated fibroblasts in targeted therapies and drug resistance in breast cancer. Front Oncol 2024; 13:1333839. [PMID: 38273859 PMCID: PMC10810416 DOI: 10.3389/fonc.2023.1333839] [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: 11/06/2023] [Accepted: 12/11/2023] [Indexed: 01/27/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs) play a substantial role in the tumor microenvironment, exhibiting a strong association with the advancement of various types of cancer, including breast, pancreatic, and prostate cancer. CAFs represent the most abundant mesenchymal cell population in breast cancer. Through diverse mechanisms, including the release of cytokines and exosomes, CAFs contribute to the progression of breast cancer by influencing tumor energy metabolism, promoting angiogenesis, impairing immune cell function, and remodeling the extracellular matrix. Moreover, CAFs considerably impact the response to treatment in breast cancer. Consequently, the development of interventions targeting CAFs has emerged as a promising therapeutic approach in the management of breast cancer. This article provides an analysis of the role of CAFs in breast cancer, specifically in relation to diagnosis, treatment, drug resistance, and prognosis. The paper succinctly outlines the diverse mechanisms through which CAFs contribute to the malignant behavior of breast cancer cells, including proliferation, invasion, metastasis, and drug resistance. Furthermore, the article emphasizes the potential of CAFs as valuable tools for early diagnosis, targeted therapy, treatment resistance, and prognosis assessment in breast cancer, thereby offering novel approaches for targeted therapy and overcoming treatment resistance in this disease.
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Affiliation(s)
| | - Hua Hao
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
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22
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De Robertis M, Signori E. Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) Model of Colorectal Cancer. Methods Mol Biol 2024; 2773:51-58. [PMID: 38236535 DOI: 10.1007/978-1-0716-3714-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
Recent progress in developing new vaccination strategies against cancer requires the production of complex and reliable animal models reflecting the complexity of the tumors with their microenvironment. Mice can be considered a good source due to low cost and ease of being genetically modified, inoculated with tumor cell lines or treated by chemicals to induce different cancers. Despite significant limitations in modeling human cancer complexity, preclinical trials conducted in mice can efficiently contribute to understand molecular mechanisms of cancer, to closely resemble and follow carcinogenesis steps impossible to study into humans, and to test new anticancer therapies. In this chapter, we generally describe the different mouse models developed for cancer vaccines' preclinical trials. A particular focus is dedicated to a chemically-induced colorectal cancer model in use in our laboratories.
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Affiliation(s)
- Mariangela De Robertis
- Department of Biosciences, Biotechnology and Environment, University of Bari 'A. Moro', Bari, Italy
| | - Emanuela Signori
- Laboratory of Molecular Pathology and Experimental Oncology, Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, Rome, Italy.
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23
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Sa P, Mohapatra P, Swain SS, Khuntia A, Sahoo SK. Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights. Mol Pharm 2023; 20:5254-5277. [PMID: 37596986 DOI: 10.1021/acs.molpharmaceut.3c00286] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2023]
Abstract
Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.
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Affiliation(s)
- Pratikshya Sa
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad, Haryana 121001, NCR Delhi, India
| | - Priyanka Mohapatra
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad, Haryana 121001, NCR Delhi, India
| | | | - Auromira Khuntia
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad, Haryana 121001, NCR Delhi, India
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24
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Li X, Chen Y, Wang R, Lu E, Luo K, Sha X. Enhancement of cancer immunotherapy using CRT valgus tumor cell membranes coated bacterial whole peptidoglycan combined with radiotherapy. Int J Pharm 2023; 646:123430. [PMID: 37742823 DOI: 10.1016/j.ijpharm.2023.123430] [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: 07/09/2023] [Revised: 08/23/2023] [Accepted: 09/18/2023] [Indexed: 09/26/2023]
Abstract
Immunotherapy has achieved some success in preclinical and clinical studies, but the immunosuppressive tumor microenvironment (TME) leads to a low response rate of this therapy. In this paper, we describe a calreticulin (CRT) valgus CT-26 tumor cell membranes-coated bacterial whole peptidoglycan (WPG) from P. aeruginosa (CPW/SR) with a high rate of the STING agonist loading. In the construct, WPG from P. aeruginosa (P.WPG) was used as a carrier with the immunoadjuvant function while synergistically promoting the maturation of dendritic cells (DCs) through the delivery of the STING agonist SR-717. CRT valgus tumor cell membranes were identified and internalized by DCs via CRT on the surface. In addition, this construct was able to reverse the immunosuppressive TME in vivo and achieve synergies with radiotherapy by creating a personalized tumor vaccine, therefore achieving more resultful antitumor efficacy. In conclusion, CPW/SR constructed in this paper provides a new approach for achieving efficient cancer immunotherapy and combination therapy.
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Affiliation(s)
- Xinhong Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yiting Chen
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Rui Wang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Enhao Lu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Kuankuan Luo
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Xianyi Sha
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China; The Institutes of Integrative Medicine of Fudan University, Shanghai, China.
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Zheng X, Jiang Q, Han M, Ye F, Wang M, Qiu Y, Wang J, Gao M, Hou F, Wang H. FBXO38 regulates macrophage polarization to control the development of cancer and colitis. Cell Mol Immunol 2023; 20:1367-1378. [PMID: 37821621 PMCID: PMC10616184 DOI: 10.1038/s41423-023-01081-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 08/27/2023] [Indexed: 10/13/2023] Open
Abstract
Macrophages are highly plastic cells that differentially regulate multiple pathological conditions, including cancer and autoimmune diseases. In response to various stimuli, macrophages activate different intrinsic signaling pathways and polarize into distinct macrophage subsets. We aimed to identify key new effectors that could control macrophage polarization and impact the development of cancer or colitis. Following treatment with the supernatants of tumor cells, macrophages showed an upregulation in Fbxo38 expression. Subsequently, we further identified that FBXO38 promotes macrophage immunosuppressive function by upregulating the expression of M2-like genes via MAPK and IRF4 signaling without affecting M1-like macrophage polarization. Deletion of Fbxo38 in macrophages was found to block tumor development and protect against DSS-induced colitis. Considering the distinct regulation of tumor development by FBXO38 in T cells and macrophages, we suggest that a comprehensive understanding of FBXO38 function in different cell types is critical for its further translational usage.
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Affiliation(s)
- Xin Zheng
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Qi Jiang
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Mingshun Han
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Fenfen Ye
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Mingchang Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ying Qiu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jialu Wang
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Minxia Gao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Fajian Hou
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Hongyan Wang
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
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Hao L, Li S, Hu X. New insights into T-cell exhaustion in liver cancer: from mechanism to therapy. J Cancer Res Clin Oncol 2023; 149:12543-12560. [PMID: 37423958 DOI: 10.1007/s00432-023-05083-5] [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: 05/29/2023] [Accepted: 06/29/2023] [Indexed: 07/11/2023]
Abstract
Liver cancer is one of the most common malignancies. T-cell exhaustion is associated with immunosuppression of tumor and chronic infection. Although immunotherapies that enhance the immune response by targeting programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) have been applied to malignancies, these treatments have shown limited response rates. This suggested that additional inhibitory receptors (IRs) also contributed to T-cell exhaustion and tumor prognosis. Exhausted T-cells (Tex) in the tumor immune microenvironment (TME) are usually in a dysfunctional state of exhaustion, such as impaired activity and proliferative ability, increased apoptosis rate, and reduced production of effector cytokines. Tex cells participate in the negative regulation of tumor immunity mainly through IRs on the cell surface, changes in cytokines and immunomodulatory cell types, causing tumor immune escape. However, T-cell exhaustion is not irreversible and targeted immune checkpoint inhibitors (ICIs) can effectively reverse the exhaustion of T-cells and restore the anti-tumor immune response. Therefore, the research on the mechanism of T-cell exhaustion in liver cancer, aimed at maintaining or restoring the effector function of Tex cells, might provide a new method for the treatment of liver cancer. In this review, we summarized the basic characteristics of Tex cells (such as IRs and cytokines), discussed the mechanisms associated with T-cell exhaustion, and specifically discussed how these exhaustion characteristics were acquired and shaped by key factors within TME. Then new insights into the molecular mechanism of T-cell exhaustion suggested a potential way to improve the efficacy of cancer immunotherapy, namely to restore the effector function of Tex cells. In addition, we also reviewed the research progress of T-cell exhaustion in recent years and provided suggestions for further research.
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Affiliation(s)
- Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Shenghao Li
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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Nafea H, Youness RA, Dawoud A, Khater N, Manie T, Abdel-Kader R, Bourquin C, Szabo C, Gad MZ. Dual targeting of H 2S synthesizing enzymes; cystathionine β-synthase and cystathionine γ-lyase by miR-939-5p effectively curbs triple negative breast cancer. Heliyon 2023; 9:e21063. [PMID: 37916110 PMCID: PMC10616356 DOI: 10.1016/j.heliyon.2023.e21063] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 10/08/2023] [Accepted: 10/13/2023] [Indexed: 11/03/2023] Open
Abstract
Introduction Hydrogen sulfide (H2S) has been recently scrutinized for its critical role in aggravating breast cancer (BC) tumorigenicity. Several cancers aberrantly express H2S synthesizing enzymes; Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). However, their levels and interdependence in BC require further studies. Objectives Firstly, this study aimed to demonstrate a comparative expression profile of H2S synthesizing enzymes in BC vs normal tissue. Moreover, to investigate the reciprocal relationship between CBS and CSE and highlight the importance of dual targeting. Finally, to search for a valid dual repressor of the H2S synthesizing enzymes that could cease H2S production and reduce TNBC pathogenicity. Methods Pairwise analysis of tumor vs. normal tissues of 40 BC patients was carried out. The TNBC cell line MDA-MB-231 was transfected with oligonucleotides to study the H2S mediated molecular mechanisms. In silico screening was performed to identify dual regulator(s) for CBS and CSE. Gene expression analysis was performed using qRT-PCR and was confirmed on protein level using Western blot. TNBC hallmarks were evaluated using MTT, migration, and clonogenicity assays. H2S levels were detected using a AzMc fluorescent probe. Results BC tissues exhibited elevated levels of both CBS and CSE. Interestingly, upon CBS knockdown, CSE levels increased compensating for H2S production in TNBC cells, underlining the importance of dually targeting both enzymes in TNBC. In silico screening suggested miR-939-5p as a regulator of both CBS and CSE with high binding scores. Low expression levels of miR-939-5p were found in BC tissues, especially the aggressive subtypes. Ectopic expression of miR-939-5p significantly repressed CBS and CSE transcript and protein levels, diminished H2S production and attenuated TNBC hallmarks. Moreover, it improved the immune surveillance potency of TNBC cells through up regulating the NKG2D ligands, MICB and ULBP2 and reducing the immune suppressive cytokine IL-10. Conclusion This study sheds light on the reciprocal relationship between CBS and CSE and on the importance of their dual targeting, particularly in TNBC. It also postulates miR-939-5p as a potent dual repressor for CBS and CSE overcoming their redundancy in H2S production, a mechanism that can potentially attenuate TNBC oncogenicity and improves the immunogenic response.
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Affiliation(s)
- Heba Nafea
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Rana A. Youness
- Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
- Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt
| | - Alyaa Dawoud
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Nour Khater
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Tamer Manie
- Breast Surgery Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Reham Abdel-Kader
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Carole Bourquin
- School of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences of Western Switzerland and Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University of Geneva, Geneva 1211, Switzerland
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Guo Y, Gao F, Ahmed A, Rafiq M, Yu B, Cong H, Shen Y. Immunotherapy: cancer immunotherapy and its combination with nanomaterials and other therapies. J Mater Chem B 2023; 11:8586-8604. [PMID: 37614168 DOI: 10.1039/d3tb01358h] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Immunotherapy is a new type of tumor treatment after surgery, radiotherapy and chemotherapy, and can be used to manage and destroy tumor cells through activating or strengthening the immune response. Immunotherapy has the benefits of a low recurrence rate and high specificity compared to traditional treatment methods. Immunotherapy has developed rapidly in recent years and has become a research hotspot. Currently, chimeric antigen receptor T-cell immunotherapy and immune checkpoint inhibitors are the most effective tumor immunotherapies in clinical practice. While tumor immunotherapy brings hope to patients, it also faces some challenges and still requires continuous research and progress. Combination therapy is the future direction of anti-tumor treatment. In this review, the main focus is on an overview of the research progress of immune checkpoint inhibitors, cellular therapies, tumor vaccines, small molecule inhibitors and oncolytic virotherapy in tumor treatment, as well as the combination of immunotherapy with other treatments.
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Affiliation(s)
- Yuanyuan Guo
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Fengyuan Gao
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Adeel Ahmed
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Muhammad Rafiq
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Bing Yu
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
- State Key Laboratory of Bio-Fibers and Eco-Textiles, Qingdao University, Qingdao 266071, China
| | - Hailin Cong
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
- State Key Laboratory of Bio-Fibers and Eco-Textiles, Qingdao University, Qingdao 266071, China
- School of Materials Science and Engineering, Shandong University of Technology, Zibo 255000, China
| | - Youqing Shen
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Center for Bionanoengineering, and Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China
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Jin Z, Zhou Q, Cheng JN, Jia Q, Zhu B. Heterogeneity of the tumor immune microenvironment and clinical interventions. Front Med 2023; 17:617-648. [PMID: 37728825 DOI: 10.1007/s11684-023-1015-9] [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: 02/15/2023] [Accepted: 06/24/2023] [Indexed: 09/21/2023]
Abstract
The tumor immune microenvironment (TIME) is broadly composed of various immune cells, and its heterogeneity is characterized by both immune cells and stromal cells. During the course of tumor formation and progression and anti-tumor treatment, the composition of the TIME becomes heterogeneous. Such immunological heterogeneity is not only present between populations but also exists on temporal and spatial scales. Owing to the existence of TIME, clinical outcomes can differ when a similar treatment strategy is provided to patients. Therefore, a comprehensive assessment of TIME heterogeneity is essential for developing precise and effective therapies. Facilitated by advanced technologies, it is possible to understand the complexity and diversity of the TIME and its influence on therapy responses. In this review, we discuss the potential reasons for TIME heterogeneity and the current approaches used to explore it. We also summarize clinical intervention strategies based on associated mechanisms or targets to control immunological heterogeneity.
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Affiliation(s)
- Zheng Jin
- Department of Oncology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Key Laboratory of Tumor Immunotherapy, Chongqing, 400037, China
- Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co. Ltd., Shanghai, 201318, China
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Qin Zhou
- Department of Oncology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
- Key Laboratory of Tumor Immunotherapy, Chongqing, 400037, China
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Jia-Nan Cheng
- Department of Oncology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
- Key Laboratory of Tumor Immunotherapy, Chongqing, 400037, China.
| | - Qingzhu Jia
- Department of Oncology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
- Key Laboratory of Tumor Immunotherapy, Chongqing, 400037, China.
| | - Bo Zhu
- Department of Oncology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
- Key Laboratory of Tumor Immunotherapy, Chongqing, 400037, China.
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Samnani S, Sachedina F, Gupta M, Guo E, Navani V. Mechanisms and clinical implications in renal carcinoma resistance: narrative review of immune checkpoint inhibitors. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:416-429. [PMID: 37457122 PMCID: PMC10344724 DOI: 10.20517/cdr.2023.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/25/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma. The prognosis for patients with ccRCC has improved over recent years with the use of combination therapies with an anti-programmed death-1 (PD-1) backbone. This has enhanced the quality of life and life expectancy of patients with this disease. Unfortunately, not all patients benefit; eventually, most patients will develop resistance to therapy and progress. Recent molecular, biochemical, and immunological research has extensively researched anti-angiogenic and immune-based treatment resistance mechanisms. This analysis offers an overview of the principles underpinning the resistance pathways related to immune checkpoint inhibitors (ICIs). Additionally, novel approaches to overcome resistance that may be considered for the trial context are discussed.
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Affiliation(s)
- Sunil Samnani
- Department of Internal Medicine, The University of Calgary, Calgary T2N 1N4, Canada
| | - Faraz Sachedina
- Department of Internal Medicine, The University of Calgary, Calgary T2N 1N4, Canada
| | - Mehul Gupta
- Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, Canada
| | - Edward Guo
- Cumming School of Medicine, University of Calgary, Calgary T2N 4N1, Canada
| | - Vishal Navani
- Department of Medical Oncology, Tom Baker Cancer Centre, Calgary T2N 4N2, Canada
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Sammarco E, Manfredi F, Nuzzo A, Ferrari M, Bonato A, Salfi A, Serafin D, Zatteri L, Antonuzzo A, Galli L. Immune Checkpoint Inhibitor Rechallenge in Renal Cell Carcinoma: Current Evidence and Future Directions. Cancers (Basel) 2023; 15:3172. [PMID: 37370782 DOI: 10.3390/cancers15123172] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Immune checkpoint inhibitor-based therapies represent the current standard of care in the first-line treatment of advanced renal cell carcinoma. Despite a clear benefit in survival outcomes, a considerable proportion of patients experience disease progression; prospective data about second-line therapy after first-line treatment with immune checkpoint inhibitors are limited to small phase II studies. As with other solid tumors (such as melanoma and non-small cell lung cancer), preliminary data about the clinical efficacy of rechallenge of immunotherapy (alone or in combination with other drugs) in renal cell carcinoma are beginning to emerge. Nevertheless, the role of rechallenge in immunotherapy in this setting of disease remains unclear and cannot be considered a standard of care; currently some randomized trials are exploring this approach in patients with metastatic renal cell carcinoma. The aim of our review is to summarize main evidence available in the literature concerning immunotherapy rechallenge in renal carcinoma, especially focusing on biological rationale of resistance to immune checkpoint inhibitors, on the published data of clinical efficacy and on future perspectives.
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Affiliation(s)
- Enrico Sammarco
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Fiorella Manfredi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Amedeo Nuzzo
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Marco Ferrari
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Adele Bonato
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Alessia Salfi
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Debora Serafin
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Luca Zatteri
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Andrea Antonuzzo
- Unit of Medical Oncology 1, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
| | - Luca Galli
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Santa Chiara Hospital, 56126 Pisa, Italy
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Liu D, Li K, Gong L, Fu L, Yang D. Charge reversal yolk-shell liposome co-loaded JQ1 and doxorubicin with high drug loading and optimal ratio for synergistically enhanced tumor chemo-immunotherapy via blockade PD-L1 pathway. Int J Pharm 2023; 635:122728. [PMID: 36796659 DOI: 10.1016/j.ijpharm.2023.122728] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/24/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023]
Abstract
Antitumor immunotherapy has become a powerful therapeutic modality to identify and kill various malignant tumors by harnessing the immune system. However, it is hampered by the immunosuppressive microenvironment and poor immunogenicity in malignant tumors. Herein, in order to achieve multi-loading of drugs with different pharmacokinetic properties and targets, a charge reversal yolk-shell liposome co-loaded with JQ1 and doxorubicin (DOX) into the poly (D,L-lactic-co-glycolic acid) (PLGA) yolk and the lumen of the liposome respectively was engineered to increase hydrophobic drug loading capacity and stability under physiological conditions and further enhance tumor chemotherapy via blockade programmed death ligand 1 (PD-L1) pathway. This nanoplatform could release less JQ1 compared to traditional liposomes to avoid drug leakage under physiological conditions due to the protection of liposomes on JQ1 loaded PLGA nanoparticles while the release of JQ1 increased in an acidic environment. In the tumor microenvironment, released DOX promoted immunogenic cell death (ICD), and JQ1 blocked the PD-L1 pathway to strengthen chemo-immunotherapy. The in vivo antitumor results demonstrated the collaborative treatment of DOX and JQ1 in B16-F10 tumor-bearing mice models with minimized systemic toxicity. Furthermore, the orchestrated yolk-shell nanoparticle system could enhance the ICD effect, caspase 3 activation, and cytotoxic T lymphocyte infiltration while inhibiting PD-L1 expression, provoking a strong antitumor effect, whereas yolk-shell liposomes encapsulating only JQ1 or DOX showed modest tumor therapeutic effects. Hence, the cooperative yolk-shell liposome strategy provides a potential candidate for enhancement of hydrophobic drug loading and stability, showing potential for clinic application and synergistic cancer chemo-immunotherapy.
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Affiliation(s)
- Dechun Liu
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127, West Youyi Road, Xi'an, Shaanxi 710072, China.
| | - Kunwei Li
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127, West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Linlin Gong
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127, West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Luyao Fu
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127, West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Dan Yang
- Department of Pharmaceutical Sciences, School of Biological and Pharmaceutical Sciences, Shaanxi University of Science and Technology, Weiyang University Park, Xi'an 710021, China
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Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol 2023; 14:1133308. [PMID: 36845131 PMCID: PMC9950271 DOI: 10.3389/fimmu.2023.1133308] [Citation(s) in RCA: 108] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.
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Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Zhu S, Wang Y, Tang J, Cao M. Radiotherapy induced immunogenic cell death by remodeling tumor immune microenvironment. Front Immunol 2022; 13:1074477. [PMID: 36532071 PMCID: PMC9753984 DOI: 10.3389/fimmu.2022.1074477] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/15/2022] [Indexed: 12/04/2022] Open
Abstract
Emerging evidence indicates that the induction of radiotherapy(RT) on the immunogenic cell death (ICD) is not only dependent on its direct cytotoxic effect, changes in the tumor immune microenvironment also play an important role in it. Tumor immune microenvironment (TIME) refers to the immune microenvironment that tumor cells exist, including tumor cells, inflammatory cells, immune cells, various signaling molecules and extracellular matrix. TIME has a barrier effect on the anti-tumor function of immune cells, which can inhibit all stages of anti-tumor immune response. The remodeling of TIME caused by RT may affect the degree of immunogenicity, and make it change from immunosuppressive phenotype to immunostimulatory phenotype. It is of great significance to reveal the causes of immune escape of tumor cells, especially for the treatment of drug-resistant tumor. In this review, we focus on the effect of RT on the TIME, the mechanism of RT in reversing the TIME to suppress intrinsic immunity, and the sensitization effect of the remodeling of TIME caused by RT on the effectiveness of immunotherapy.
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Shen X, Zhou S, Yang Y, Hong T, Xiang Z, Zhao J, Zhu C, Zeng L, Zhang L. TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress. Front Oncol 2022; 12:1034842. [PMID: 36419877 PMCID: PMC9677115 DOI: 10.3389/fonc.2022.1034842] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
Abstract
Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. Finally, we conclude with our perspectives on the future development in this field.
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Affiliation(s)
- Xinyuan Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Shengcheng Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yidong Yang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Tu Hong
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ze Xiang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jing Zhao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Chaojie Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Linghui Zeng
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Lingxiao Zhang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
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36
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Peng JM, Chiu CF, Cheng JH, Liu HY, Chang YL, Luo JW, Weng YT, Luo HL. Evasion of NK cell immune surveillance via the vimentin-mediated cytoskeleton remodeling. Front Immunol 2022; 13:883178. [PMID: 36032170 PMCID: PMC9402923 DOI: 10.3389/fimmu.2022.883178] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 07/22/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer immunotherapy uses the immune system to achieve therapeutic effects; however, its effect is still limited. Therefore, in addition to immune checkpoint-based treatment, the development of other strategies that can inhibit cancer cells from resisting immune cytotoxicity is important. There are currently few studies on the mechanism of tumors using cytoskeletal proteins reorganization to participate in immune escape. In this study, we identified cancer cell lines that were sensitive or resistant to natural killer cells in urothelial and lung cancer using the natural killer cell sensitivity assay. We found that immunoresistant cancer cells avoid natural killer cell-mediated cytotoxicity by upregulation of vimentin and remodeling of actin cytoskeleton. Immunofluorescence staining showed that immune cells promoted the formation of actin filaments at the immune synapse, which was not found in immunosensitive cancer cells. Pretreatment of the actin polymerization inhibitors latrunculin B increased the cytotoxicity of natural killer cells, suggesting that cytoskeleton remodeling plays a role in resisting immune cell attack. In addition, silencing of vimentin with shRNA potentiated the cytotoxicity of natural killer cells. Interestingly, the upregulation and extension of vimentin was found in tumor islands of upper tract urothelial carcinoma infiltrated by natural killer cells. Conversely, tumors without natural killer cell invasion showed less vimentin signal. The expression level of vimentin was highly correlated with natural killer cell infiltration. In summary, we found that when immune cells attack cancer cells, the cancer cells resist immune cytotoxicity through upregulated vimentin and actin reorganization. In addition, this immune resistance mechanism was also found in patient tumors, indicating the possibility that they can be applied to evaluate the immune response in clinical diagnosis.
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Affiliation(s)
- Jei-Ming Peng
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- *Correspondence: Jei-Ming Peng, ; ; Hao-Lun Luo,
| | - Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan
| | - Jai-Hong Cheng
- Center for Shockwave Medicine and Tissue Engineering, Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Department of Leisure and Sports Management, Cheng Shiu University, Kaohsiung, Taiwan
| | - Hui-Ying Liu
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yin-Lun Chang
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jia-Wun Luo
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yu-Ting Weng
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Hao-Lun Luo
- Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- *Correspondence: Jei-Ming Peng, ; ; Hao-Lun Luo,
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Du Z, Feng Y, Zhang H, Liu J, Wang J. Melanoma-derived small extracellular vesicles remodel the systemic onco-immunity via disrupting hematopoietic stem cell proliferation and differentiation. Cancer Lett 2022; 545:215841. [DOI: 10.1016/j.canlet.2022.215841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/18/2022] [Accepted: 07/23/2022] [Indexed: 02/08/2023]
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Xu X, Mao H, Wu Y, Liu S, Liu J, Li Q, Yang M, Zhu J, Zou S, Du F. Fabrication of methylene blue-loaded ovalbumin/polypyrrole nanoparticles for enhanced phototherapy-triggered antitumour immune activation. J Nanobiotechnology 2022; 20:297. [PMID: 35733214 PMCID: PMC9214988 DOI: 10.1186/s12951-022-01507-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/14/2022] [Indexed: 08/07/2023] Open
Abstract
BACKGROUND Phototherapy-triggered immunogenic cell death (ICD) rarely elicits a robust antitumour immune response, partially due to low antigen exposure and inefficient antigen presentation. To address these issues, we developed novel methylene blue-loaded ovalbumin/polypyrrole nanoparticles (MB@OVA/PPY NPs) via oxidative polymerization and π-π stacking interactions. RESULTS The as-prepared MB@OVA/PPY NPs with outstanding photothermal conversion efficiency (38%) and photodynamic properties were readily internalized into the cytoplasm and accumulated in the lysosomes and mitochondria. Upon 808 nm and 660 nm laser irradiation, the MB@OVA/PPY NPs not only ablated tumour cells by inducing local hyperthermia but also damaged residual tumour cells by generating a large amount of reactive oxygen species (ROS), finally triggering the release of many damage-associated molecular patterns (DAMPs). Moreover, the MB@OVA/PPY NPs synergized with DAMPs to promote the maturation and improve the antigen presentation ability of DCs in vitro and in vivo. CONCLUSIONS This work reported a PPY NPs-based nanoplatform to encapsulate the therepeutic proteins and absorb the functional molecules for combination therapy of tumours. The results demonstrated that the prepared MB@OVA/PPY NPs could be used as effective nanotherapeutic agents to eliminate solid tumours and trigger a powerful antitumour immune response.
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Affiliation(s)
- Xiao Xu
- Affiliated Third Hospital of Zhenjiang, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Huafen Mao
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China.,Lianyungang Maternal and Child Health Hospital, Lianyungang, 222000, People's Republic of China
| | - Yunchao Wu
- Clinical Laboratory, The Third People's Hospital of Changzhou, Changzhou, 213001, People's Republic of China
| | - Suwan Liu
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Jingjin Liu
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Qianzhe Li
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Mengyu Yang
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Jinqian Zhu
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Shengqiang Zou
- Affiliated Third Hospital of Zhenjiang, Jiangsu University, Zhenjiang, 212013, People's Republic of China
| | - Fengyi Du
- School of Medicine, Jiangsu University, Zhenjiang, 212013, People's Republic of China.
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Yan T, Yu L, Zhang N, Peng C, Su G, Jing Y, Zhang L, Wu T, Cheng J, Guo Q, Shi X, Lu Y. The advanced development of molecular targeted therapy for hepatocellular carcinoma. Cancer Biol Med 2022. [PMID: 35699406 DOI: 10.20892/j.issn.2095-3941.2021.0661.pmid:35699406;pmcid:pmc9257319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most common malignant tumors in China, severely threatens the life and health of patients. In recent years, precision medicine, clinical diagnoses, treatments, and innovative research have led to important breakthroughs in HCC care. The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC. Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment. Multiomics technologies, such as genomics, transcriptomics, and metabolomics, have enabled deeper understanding of the occurrence and development mechanisms, heterogeneity, and genetic mutation characteristics of HCC. The continued promotion and accurate typing of HCC, accurate guidance of treatment, and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC. Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.
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Affiliation(s)
- Tao Yan
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Lingxiang Yu
- The Second Department of Hepatobiliary Surgery, Senior Department of Hepatology, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ning Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Caiyun Peng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Guodong Su
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yi Jing
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Linzhi Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Tong Wu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jiamin Cheng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Qian Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | | | - Yinying Lu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- National Clinical Medical Research Center for Infectious Diseases, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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40
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Yan T, Yu L, Zhang N, Peng C, Su G, Jing Y, Zhang L, Wu T, Cheng J, Guo Q, Shi X, Lu Y. The advanced development of molecular targeted therapy for hepatocellular carcinoma. Cancer Biol Med 2022; 19:j.issn.2095-3941.2021.0661. [PMID: 35699406 PMCID: PMC9257319 DOI: 10.20892/j.issn.2095-3941.2021.0661] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/18/2022] [Indexed: 11/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most common malignant tumors in China, severely threatens the life and health of patients. In recent years, precision medicine, clinical diagnoses, treatments, and innovative research have led to important breakthroughs in HCC care. The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC. Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment. Multiomics technologies, such as genomics, transcriptomics, and metabolomics, have enabled deeper understanding of the occurrence and development mechanisms, heterogeneity, and genetic mutation characteristics of HCC. The continued promotion and accurate typing of HCC, accurate guidance of treatment, and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC. Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.
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Affiliation(s)
- Tao Yan
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Lingxiang Yu
- The Second Department of Hepatobiliary Surgery, Senior Department of Hepatology, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Ning Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Caiyun Peng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Guodong Su
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yi Jing
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Linzhi Zhang
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Tong Wu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jiamin Cheng
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Qian Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | | | - Yinying Lu
- Comprehensive Liver Cancer Center, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- National Clinical Medical Research Center for Infectious Diseases, the 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Yu Q, Zhao L, Yan XX, Li Y, Chen XY, Hu XH, Bu Q, Lv XP. Identification of a TGF-β signaling-related gene signature for prediction of immunotherapy and targeted therapy for lung adenocarcinoma. World J Surg Oncol 2022; 20:183. [PMID: 35668494 PMCID: PMC9172180 DOI: 10.1186/s12957-022-02595-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/16/2022] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Transforming growth factor (TGF)-β signaling functions importantly in regulating tumor microenvironment (TME). This study developed a prognostic gene signature based on TGF-β signaling-related genes for predicting clinical outcome of patients with lung adenocarcinoma (LUAD). METHODS TGF-β signaling-related genes came from The Molecular Signature Database (MSigDB). LUAD prognosis-related genes were screened from all the genes involved in TGF-β signaling using least absolute shrinkage and selection operator (LASSO) Cox regression analysis and then used to establish a risk score model for LUAD. ESTIMATE and CIBERSORT analyzed infiltration of immune cells in TME. Immunotherapy response was analyzed by the TIDE algorithm. RESULTS A LUAD prognostic 5-gene signature was developed based on 54 TGF-β signaling-related genes. Prognosis of high-risk patients was significantly worse than low-risk patients. Both internal validation and external dataset validation confirmed a high precision of the risk model in predicting the clinical outcomes of LUAD patients. Multivariate Cox analysis demonstrated the model independence in OS prediction of LUAD. The risk model was significantly related to the infiltration of 9 kinds of immune cells, matrix, and immune components in TME. Low-risk patients tended to respond more actively to anti-PD-1 treatment, while high-risk patients were more sensitive to chemotherapy and targeted therapy. CONCLUSIONS The 5-gene signature based on TGF-β signaling-related genes showed potential for LUAD management.
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Affiliation(s)
- Qian Yu
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China
| | - Liang Zhao
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China
| | - Xue-Xin Yan
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China
| | - Ye Li
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China
| | - Xin-Yu Chen
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China
| | - Xiao-Hua Hu
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China.
| | - Qing Bu
- Department of Oncology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China.
| | - Xiao-Ping Lv
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6 Shuangyong Rd, Nanning, 450100, China.
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Wang W, He J, Yang J, Zhang C, Cheng Z, Zhang Y, Zhang Q, Wang P, Tang S, Wang X, Liu M, Lu W, Zhang HK. Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy. J Med Chem 2022; 65:7896-7917. [PMID: 35640059 DOI: 10.1021/acs.jmedchem.2c00448] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Cancer cells can effectively suppress the natural immune response in humans, and prostaglandin E2 (PGE2) is a key mediator in the development of tumor cell resistance to immunotherapy. As a major contributor to PGE2-elicited immunosuppressive activity, the EP4 receptor promotes tumor development and progression in the tumor microenvironment, and the development of selective and potent EP4 receptor antagonists should have promising potential for tumor immunotherapy. Aiming at improving the drug-like properties, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives were designed and synthesized through a scaffold hopping strategy. The most promising compound 47 exhibited good EP4 antagonistic activity and excellent subtype selectivity, as well as favorable drug-like properties. It effectively suppressed the expression of multiple immunosuppression-related genes in macrophages. Meanwhile, oral administration of compound 47, alone or in combination with anti-PD-1 antibody, significantly enhanced the antitumor immune response and inhibited tumor growth in the mouse CT26 colon carcinoma model.
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Affiliation(s)
- Wei Wang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Jiacheng He
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Junjie Yang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Chan Zhang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Zhiyuan Cheng
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Yao Zhang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Qiansen Zhang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Peili Wang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Shuowen Tang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Xin Wang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Mingyao Liu
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Weiqiang Lu
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
| | - Han-Kun Zhang
- Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
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Luo R, Li Y, Wu Z, Zhang Y, Luo J, Yang K, Qin X, Wang H, Huang R, Wang H, Luo H. Comprehensive Analysis of Microsatellite-Related Transcriptomic Signature and Identify Its Clinical Value in Colon Cancer. Front Surg 2022; 9:871823. [PMID: 35433823 PMCID: PMC9008782 DOI: 10.3389/fsurg.2022.871823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/03/2022] [Indexed: 12/03/2022] Open
Abstract
Background Microsatellite has been proved to be an important prognostic factor and a treatment reference in colon cancer. The transcriptome profile and tumor microenvironment of different microsatellite statuses are different. Metastatic colon cancer patients with microsatellite instability-high (MSI-H) are sensitive to immune checkpoint inhibitors (ICIs), but not fluorouracil. Efforts have been devoted to identify the predictive factors of immunotherapy. Methods We analyzed the transcriptome profile of different microsatellite statuses in colon cancer by using single-cell and bulk transcriptome data from publicly available databases. The immune cells in the tumor microenvironment were analyzed by the ESTIMATION algorithm. The microsatellite-related gene signature (MSRS) was constructed by the least absolute shrinkage and selection operator (LASSO) Cox regression based on the differentially expressed genes (DEGs) and its prognostic value and predictive value of response to immunotherapy were assessed. The prognostic value of the MSRS was also validated in another cohort. Results The MSI-H cancers cells were clustered differentially in the dimension reduction plot. Most of the immune cells have a higher proportion in the tumor immune microenvironment, except for CD56 bright natural killer cells. A total of 238 DEGs were identified. Based on the 238 DEGs, a neural network was constructed with a Kappa coefficient of 0.706 in the testing cohort. The MSRS is a favorable prognostic factor of overall survival, which was also validated in another cohort (GSE39582). Besides, MSRS is correlated with tumor mutation burden in MSI-H colon cancer. However, the MSRS is a barely satisfactory factor in predicting immunotherapy with the area under the curve (AUC) of 0.624. Conclusion We developed the MSRS, which is a robust prognostic factor of overall survival in spite of a barely satisfactory immunotherapy predictor. Further studies may need to improve the predictive ability.
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Affiliation(s)
- Rui Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yang Li
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhijie Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuanxin Zhang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jian Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Keli Yang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiusen Qin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Huaiming Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Rongkang Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Rongkang Huang
| | - Hui Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Hui Wang
| | - Hongzhi Luo
- Department of Tumor Surgery, Zhongshan City People's Hospital, Zhongshan, China
- Hongzhi Luo
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Kooshki L, Mahdavi P, Fakhri S, Akkol EK, Khan H. Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer. Biofactors 2022; 48:359-383. [PMID: 34724274 DOI: 10.1002/biof.1799] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022]
Abstract
Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.
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Affiliation(s)
- Leila Kooshki
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parisa Mahdavi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
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REchallenge of NIVOlumab (RENIVO) or Nivolumab-Ipilimumab in Metastatic Renal Cell Carcinoma: An Ambispective Multicenter Study. JOURNAL OF ONCOLOGY 2022; 2022:3449660. [PMID: 35222642 PMCID: PMC8881133 DOI: 10.1155/2022/3449660] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/06/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
Abstract
Introduction. Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. Results. ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8–23.5) and 3.5 months (95% CI, 2.8–9.7), and median overall survival was not reached (NR) (95% CI, 37.8–NR) and 24 months (95% CI, 9.9–NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months (
) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens (
). Conclusion. Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.
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Bi Z, Li W, Zhao J, Pang L, Jing Y, Zhang X, Yao S, Yin X, Zuo H, Cheng H. Negative correlations of psychological distress with quality of life and immunotherapy efficacy in patients with advanced NSCLC. Am J Cancer Res 2022; 12:805-815. [PMID: 35261803 PMCID: PMC8899984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/07/2022] [Indexed: 06/14/2023] Open
Abstract
To evaluate the relationships between psychological distress and immunotherapy efficacy, adverse reactions and quality of life scores in patients with advanced non-small cell lung cancer (NSCLC). A total of 104 NSCLC patients who received 4-6 cycles of standard immunotherapy were enrolled and evaluated with the Distress Thermometer (DT) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The aim was to analyze the correlation between psychological distress and quality of life and to analyze whether psychological distress affects the efficacy of and adverse reactions to immunotherapy. The objective response rate (ORR) and disease control rate (DCR) of the psychological distress group were 6% and 50%, respectively, and those of the no psychological distress group were 18.5% and 83.3%, respectively. The differences were statistically significant (χ2=14.131, P<0.05). The progression-free survival (PFS) of advanced NSCLC patients who received comprehensive immunotherapy and had no psychological distress was significantly better than that of the psychological distress group (HR, 0.338; 95% CI, 0.192-0.592; P<0.05). The PFS of advanced NSCLC patients who received immunotherapy combined with chemotherapy in the no psychological distress group was significantly better than that in the psychological distress group (HR, 0.458; 95% CI, 0.296-0.709; P<0.05). Psychological distress in advanced NSCLC patients affects the efficacy of immunotherapy, and psychological distress is negatively correlated with quality of life during immunotherapy.
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Affiliation(s)
- Ziran Bi
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Wen Li
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Jie Zhao
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Lulian Pang
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Yanyan Jing
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Xiuqing Zhang
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Senbang Yao
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Xiangxiang Yin
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - He Zuo
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
| | - Huaidong Cheng
- Cancer Treatment Center, The Second Affiliated Hospital of Anhui Medical University Hefei 230601, Anhui, China
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Liu X, Hoft DF, Peng G. Tumor microenvironment metabolites directing T cell differentiation and function. Trends Immunol 2022; 43:132-147. [PMID: 34973923 PMCID: PMC8810659 DOI: 10.1016/j.it.2021.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/03/2021] [Accepted: 12/05/2021] [Indexed: 02/03/2023]
Abstract
Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions.
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Affiliation(s)
- Xia Liu
- Division of Infectious Diseases, Allergy and Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
| | - Daniel F Hoft
- Division of Infectious Diseases, Allergy and Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, MO 63104, USA
| | - Guangyong Peng
- Division of Infectious Diseases, Allergy and Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, MO 63104, USA.
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Robustness of Propofol and Sevoflurane on the Perioperative Immune Function of Patients Undergoing Laparoscopic Radical Nephrectomy. JOURNAL OF ONCOLOGY 2022; 2022:1662007. [PMID: 35136408 PMCID: PMC8818401 DOI: 10.1155/2022/1662007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 01/02/2023]
Abstract
Objective. This study aimed to evaluate the robustness of propofol combined with sevoflurane in patients undergoing laparoscopic radical nephrectomy and its influence on immune function during perioperative period. A total of 140 patients who underwent laparoscopic nephrectomy in the Department of Oncology of our hospital from January 2018 to January 2020 were divided into the control group and the study group by the random number table method, with 70 cases in each group, who were given sevoflurane anesthesia and sevoflurane combined with propofol anesthesia, respectively. The anesthesia effect and perioperative immune function of the two groups of patients were compared. No remarkable difference was observed in the extubation time, breathing recovery time, and awakening time between the two groups; the extubation coughing score and postextubation restlessness score of the study group were significantly lower than those of the control group; the postoperative renal function indexes of the two groups of patients were not considerably different; after treatment, the CD3+ (%), CD4+ (%), and CD4+/CD8+ of the two groups of patients decreased significantly, with a higher level in the study group. For patients undergoing laparoscopic radical nephrectomy, the combination of propofol and sevoflurane yields a promising outcome in enhancing the anesthesia results and improving the perioperative immune function.
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Zhang J, Veeramachaneni N. Targeting interleukin-1β and inflammation in lung cancer. Biomark Res 2022; 10:5. [PMID: 35086565 PMCID: PMC8796434 DOI: 10.1186/s40364-021-00341-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/03/2021] [Indexed: 12/16/2022] Open
Abstract
Inflammation is a process that protects organs against various potentially harmful stimuli and enables repair. Dysregulated inflammation, however, damages tissues and leads to disease, including cancer. Cancer-related inflammation is characterized by cytokine production, leukocyte infiltration, angiogenesis, and tissue remodeling-all critical processes in modulating the tumor microenvironment (TME). The TME is known to play a key role in tumor progression, and targeting its immune component to achieve a better anti-tumor response is the basis of immunotherapy. Despite the critical role cytokines play in the TME and tumor progression, there is currently only one therapy approved by the FDA that directly involves cytokine signaling: human recombinant interleukin-2 protein, aldesleukin. The recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial evaluated the use of anti-interleukin-1β therapy in atherosclerotic disease; however, it also revealed interleukin-1β (IL-1β) blockade with canakinumab led to a significantly lower incidence of lung cancer. This has opened a promising new avenue for lung cancer therapy, and strategies using anti-IL-1β therapy alone or in combination with chemotherapy and/or immune checkpoint blockade are currently being evaluated in several clinical trials.
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Affiliation(s)
- Jun Zhang
- Division of Medical Oncology, Department of Internal Medicine, Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA.
| | - Nirmal Veeramachaneni
- Department of Cardiovascular and Thoracic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160 , USA
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Therapeutic exosomal vaccine for enhanced cancer immunotherapy by mediating tumor microenvironment. iScience 2022; 25:103639. [PMID: 35024580 PMCID: PMC8724970 DOI: 10.1016/j.isci.2021.103639] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/21/2021] [Accepted: 12/13/2021] [Indexed: 01/15/2023] Open
Abstract
Tumor immunotherapy has been convincingly demonstrated as a feasible approach for treating cancers. Although promising, the immunosuppressive tumor microenvironment (TME) has been recognized as a major obstacle in tumor immunotherapy. It is highly desirable to release an immunosuppressive "brake" for improving cancer immunotherapy. Among tumor-infiltrated immune cells, tumor-associated macrophages (TAMs) play an important role in the growth, invasion, and metastasis of tumors. The polarization of TAMs (M2) into the M1 type can alleviate the immunosuppression of the TME and enhance the effect of immunotherapy. Inspired by this, we constructed a therapeutic exosomal vaccine from antigen-stimulated M1-type macrophages (M1OVA-Exos). M1OVA-Exos are capable of polarizing TAMs into M1 type through downregulation of the Wnt signaling pathway. Mediating the TME further activates the immune response and inhibits tumor growth and metastasis via the exosomal vaccine. Our study provides a new strategy for the polarization of TAMs, which augments cancer vaccine therapy efficacy.
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