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Tong M, Xu Z, Wang L, Chen H, Wan X, Xu H, Yang S, Tu Q. An analysis of prognostic risk and immunotherapy response of glioblastoma patients based on single-cell landscape and nitrogen metabolism. Neurobiol Dis 2025; 211:106935. [PMID: 40348204 DOI: 10.1016/j.nbd.2025.106935] [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: 01/14/2025] [Revised: 04/03/2025] [Accepted: 04/28/2025] [Indexed: 05/14/2025] Open
Abstract
Glioblastoma (GBM) is a highly invasive brain tumor of astrocytic origin. Nitrogen metabolism plays an instrumental role in the growth and progression of various tumors, including GBM. This study intended to mine nitrogen metabolism-related biomarkers for GBM-related research of prognosis and immunotherapy. Through single-cell data analysis of GBM, we identified four cell types (Astrocytes, Macrophages, Fibroblasts, and Endothelial cells). We calculated the nitrogen metabolism scores and conducted trajectory analysis for the most abundant cells, Astrocytes, revealing 6 differentiation directions of Astrocytes, which included the main differentiation direction from cells with low nitrogen metabolism scores to cells with high nitrogen metabolism scores. Furthermore, based on the differentially expressed genes (DEGs) with high/low nitrogen metabolism scores, we constructed a 7-gene prognostic model by utilizing regression analysis. qRT-PCR analysis showed that IGFBP2, CHPF, CTSZ, UPP1, TCF12, ZBTB20 and RBP1 were all significantly up-regulated in the GBM cells. Through differential analysis, a protein-protein interaction (PPI) network, and enrichment analyses, we identified and analyzed the DEGs in the high RiskScore subgroup, revealing complex interactions among DEGs, which were mainly related to pathways such as TNF signaling pathway and NF-κB signaling pathway. By leveraging univariate analysis, survival-related genes were selected from the nitrogen metabolism-related gene sets. Clustering, survival, immune, and mutation analyses manifested that the collected nitrogen metabolism-related genes had good classification performance, presenting notable differences in survival rates, immune levels, gene mutations, and sensitivity to drugs between cluster1 and cluster2. In conclusion, the project investigated the prognosis and classification value of nitrogen metabolism-related genes in GBM from multiple perspectives, predicting the sensitivity of different subtypes of patients to immunotherapy response and drug sensitivity. These findings are expected to show new research directions for further exploration in these fields.
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Affiliation(s)
- Minfeng Tong
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Zhijian Xu
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Lude Wang
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Huahui Chen
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Xing Wan
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Hu Xu
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Song Yang
- Department of Neurosurgery, Jiaozhou Branch, East Hospital Affiliated to Tongji University, Jiaozhou 266300, China.
| | - Qi Tu
- Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China.
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2
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Chao PH, Chan V, Li SD. Nanomedicines modulate the tumor immune microenvironment for cancer therapy. Expert Opin Drug Deliv 2024; 21:1719-1733. [PMID: 39354745 DOI: 10.1080/17425247.2024.2412245] [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: 08/07/2024] [Revised: 09/17/2024] [Accepted: 09/30/2024] [Indexed: 10/03/2024]
Abstract
INTRODUCTION In recent years, the evolution of immunotherapy as a means to trigger a robust antitumor immune response has revolutionized cancer treatment. Despite its potential, the effectiveness of cancer immunotherapy is hindered by low response rates and significant systemic side effects. Nanotechnology emerges as a promising frontier in shaping the future of cancer immunotherapy. AREAS COVERED This review elucidates the pivotal role of nanomedicine in reshaping the immune tumor microenvironment and explores innovative strategies pursued by diverse research groups to enhance the therapeutic efficacy of cancer immunotherapy. It discusses the hurdles encountered in cancer immunotherapy and the application of nanomedicine for small molecule immune modulators and nucleic acid therapeutics. It also highlights the advancements in DNA and mRNA vaccines facilitated by nanotechnology and outlines future trajectories in this evolving field. EXPERT OPINION Collectively, the integration of nanomedicine into cancer immunotherapy stands as a promising avenue to tackle the intricacies of the immune tumor microenvironment. Innovations such as immune checkpoint inhibitors and cancer vaccines have shown promise. Future developments will likely optimize nanoparticle design through artificial intelligence and create biocompatible, multifunctional nanoparticles, promising more effective, personalized, and durable cancer treatments, potentially transforming the field in the foreseeable future.
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Affiliation(s)
- Po-Han Chao
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Vanessa Chan
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Shyh-Dar Li
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
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3
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Mousa AM, Enk AH, Hassel JC, Reschke R. Immune Checkpoints and Cellular Landscape of the Tumor Microenvironment in Non-Melanoma Skin Cancer (NMSC). Cells 2024; 13:1615. [PMID: 39404378 PMCID: PMC11475876 DOI: 10.3390/cells13191615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/19/2024] Open
Abstract
Non-melanoma skin cancer (NMSC) is primarily categorized into basal cell carcinoma (BCC), the most prevalent form of skin cancer, and cutaneous squamous cell carcinoma (cSCC), the second most common type. Both BCC and cSCC represent a significant health burden, particularly in immunocompromised individuals and the elderly. The immune system plays a pivotal role in the development and progression of NMSC, making it a critical focus for therapeutic interventions. This review highlights key immunological targets in BCC and cSCC, with a focus on immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4, which regulate T cell activity and contribute to immune evasion. This review also highlights anti-tumor immune cell subsets within the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TILs) and dendritic cells. Additionally, it examines the immunosuppressive elements of the TME, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), as well as their roles in NMSC progression and resistance to therapy. Emerging strategies targeting these immune elements, such as monoclonal antibodies, are also discussed for their potential to enhance anti-tumor immune responses and improve clinical outcomes. By elucidating the immunological landscape of BCC and cSCC and drawing comparisons to melanoma, this review highlights the transformative potential of immunotherapy in treating these malignancies.
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Affiliation(s)
- Ahmed M. Mousa
- Department of Dermatology and National Center for Tumor Diseases (NCT), Medical Faculty Heidelberg, Heidelberg University NCT Heidelberg, a Partnership between DKFZ and University Hospital Heidelberg, 69117 Heidelberg, Germany
| | - Alexander H. Enk
- Department of Dermatology and National Center for Tumor Diseases (NCT), Medical Faculty Heidelberg, Heidelberg University NCT Heidelberg, a Partnership between DKFZ and University Hospital Heidelberg, 69117 Heidelberg, Germany
| | - Jessica C. Hassel
- Department of Dermatology and National Center for Tumor Diseases (NCT), Medical Faculty Heidelberg, Heidelberg University NCT Heidelberg, a Partnership between DKFZ and University Hospital Heidelberg, 69117 Heidelberg, Germany
- German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, 69120 Heidelberg, Germany
| | - Robin Reschke
- Department of Dermatology and National Center for Tumor Diseases (NCT), Medical Faculty Heidelberg, Heidelberg University NCT Heidelberg, a Partnership between DKFZ and University Hospital Heidelberg, 69117 Heidelberg, Germany
- German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, 69120 Heidelberg, Germany
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4
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Ozbay Kurt FG, Lasser S, Arkhypov I, Utikal J, Umansky V. Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target. J Clin Invest 2023; 133:e170762. [PMID: 37395271 DOI: 10.1172/jci170762] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023] Open
Abstract
Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.
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Affiliation(s)
- Feyza Gul Ozbay Kurt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | - Samantha Lasser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | - Ihor Arkhypov
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany
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5
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Mirjačić Martinović K, Vuletić A, Tišma Miletić N, Nedeljković M, Babović N, Matković S, Jurišić V. Increased circulating monocyte MDSCs positively correlate with serum Interleukin-10 in metastatic melanoma patients. Innate Immun 2023:17534259231172079. [PMID: 37160888 DOI: 10.1177/17534259231172079] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023] Open
Abstract
Numerous immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and inhibitory cytokines identified in melanoma microenvironment have the important role in immune escape. Therefore, in this study we analyzed monocytic (m)MDSCs in peripheral blood of metastatic melanoma (MM) patients. In peripheral blood of 35 MM patients and 30 healthy controls we analyzed percentage of CD14 + HLA-DR- mMDSCs in monocyte gate and the mean fluorescence intensity of Foxp3 in CD25 + CD4 + regulatory T cells by Flow cytometry. Serum levels of transforming growth factor beta, interferon-gamma, interleukin (IL)-6, IL-8, IL-10 are measured by ELISA assays. In this study MM patients have significantly higher percentage of CD14 + HLA-DR- mMDSCs, as well as increased the baseline mMDSC/PBMC subset (NK, T, B cells, monocytes) ratio. Although there is no significant difference in the percentage of mMDSCs between groups of MM patients with different localization of distant metastasis, patients with elevated serum lactate dehydrogenase (LDH) have statistically significant higher percentage of these cells compared to LDH negative patients. Furthermore, in MM patients there is statistically significant positive correlation between values of IL-10 and the percentage of mMDSCs, only. Therefore, therapeutics that target circulating mMDSCs and IL-10 may have a big importance in the improvement of antitumor immunity in MM patients.
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Affiliation(s)
| | - Ana Vuletić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Nevena Tišma Miletić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Milica Nedeljković
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Nada Babović
- Department of Medical Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Suzana Matković
- Department of Medical Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Vladimir Jurišić
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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6
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Ji X, Jiang W, Wang J, Zhou B, Ding W, Liu S, Huang H, Chen G, Sun X. Application of individualized multimodal radiotherapy combined with immunotherapy in metastatic tumors. Front Immunol 2023; 13:1106644. [PMID: 36713375 PMCID: PMC9877461 DOI: 10.3389/fimmu.2022.1106644] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 12/22/2022] [Indexed: 01/14/2023] Open
Abstract
Radiotherapy is one of the mainstays of cancer treatment. More than half of cancer patients receive radiation therapy. In addition to the well-known direct tumoricidal effect, radiotherapy has immunomodulatory properties. When combined with immunotherapy, radiotherapy, especially high-dose radiotherapy (HDRT), exert superior systemic effects on distal and unirradiated tumors, which is called abscopal effect. However, these effects are not always effective for cancer patients. Therefore, many studies have focused on exploring the optimized radiotherapy regimens to further enhance the antitumor immunity of HDRT and reduce its immunosuppressive effect. Several studies have shown that low-dose radiotherapy (LDRT) can effectively reprogram the tumor microenvironment, thereby potentially overcoming the immunosuppressive stroma induced by HDRT. However, bridging the gap between preclinical commitment and effective clinical delivery is challenging. In this review, we summarized the existing studies supporting the combined use of HDRT and LDRT to synergistically enhance antitumor immunity, and provided ideas for the individualized clinical application of multimodal radiotherapy (HDRT+LDRT) combined with immunotherapy.
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7
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Saeidi V, Doudican N, Carucci JA. Understanding the squamous cell carcinoma immune microenvironment. Front Immunol 2023; 14:1084873. [PMID: 36793738 PMCID: PMC9922717 DOI: 10.3389/fimmu.2023.1084873] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/13/2023] [Indexed: 01/31/2023] Open
Abstract
Primary cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with a rising incidence of about 1.8 million in the United States annually. Primary cSCC is usually curable by surgery; however, in some cases, cSCC eventuates in nodal metastasis and death from disease specific death. cSCC results in up to 15,000 deaths each year in the United States. Until recently, non-surgical options for treatment of locally advanced or metastatic cSCC were largely ineffective. With the advent of checkpoint inhibitor immunotherapy, including cemiplimab and pembrolizumab, response rates climbed to 50%, representing a vast improvement over chemotherapeutic agents used previously. Herein, we discuss the phenotype and function of SCC associated Langerhans cells, dendritic cells, macrophages, myeloid derived suppressor cells and T cells as well as SCC-associated lymphatics and blood vessels. Possible role(s) of SCC-associated cytokines in progression and invasion are reviewed. We also discuss the SCC immune microenvironment in the context of currently available and pipeline therapeutics.
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Affiliation(s)
- Vahide Saeidi
- Section of Dermatologic Surgery, Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, NY, United States
| | - Nicole Doudican
- Section of Dermatologic Surgery, Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, NY, United States
| | - John A Carucci
- Section of Dermatologic Surgery, Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, NY, United States
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8
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Colombe P, Béguin J, Benchekroun G, Le Roux D. Blood biomarkers for canine cancer, from human to veterinary oncology. Vet Comp Oncol 2022; 20:767-777. [PMID: 35815441 PMCID: PMC9796515 DOI: 10.1111/vco.12848] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 01/01/2023]
Abstract
In recent decades, interest in circulating tumour biomarkers is increasing both in human and veterinary oncology. An ideal tumour biomarker would allow early diagnosis of neoplasia, identify it specifically, accurately, establish a prognosis and predict its behaviour, especially regarding different therapeutic solutions. It would also allow to monitor its evolution over time and all this in a non-invasive and inexpensive way. Actually, no biomarkers meeting all of these criteria have been identified in veterinary medicine, particularly due to a lack of specificity of the main protein tumour biomarkers studied to date. However, great hope is currently placed in biomarkers grouped under the name of liquid biopsy, which could prove to be effective tools for common clinical use in the near future. This review gives an update on blood cancer biomarkers studied in dogs, such as ions, proteins, nucleic acids and also circulating cells, of which some might become more prominent in the coming years to help improve the management of animal care.
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Affiliation(s)
- Philippe Colombe
- Ecole Nationale Vétérinaire d'AlfortBioPôle AlfortMaisons‐AlfortFrance,Ecole Nationale Vétérinaire d'AlfortCHUVA, Service de Médecine InterneMaisons‐AlfortFrance
| | - Jérémy Béguin
- Ecole Nationale Vétérinaire d'AlfortCHUVA, Service de Médecine InterneMaisons‐AlfortFrance,Anses, INRAE, Ecole Nationale Vétérinaire d'AlfortUMR VIROLOGIE, Laboratoire de Santé AnimaleMaisons‐AlfortFrance
| | - Ghita Benchekroun
- Ecole Nationale Vétérinaire d'AlfortCHUVA, Service de Médecine InterneMaisons‐AlfortFrance,Ecole nationale Vétérinaire d'AlfortUniv Paris Est Créteil, INSERM, IMRBMaisons‐AlfortFrance
| | - Delphine Le Roux
- Ecole Nationale Vétérinaire d'AlfortBioPôle AlfortMaisons‐AlfortFrance,Anses, INRAE, Ecole Nationale Vétérinaire d'AlfortUMR BIPAR, Laboratoire de Santé AnimaleMaisons‐AlfortFrance
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9
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Son YM, Kim J. The Microbiome-Immune Axis Therapeutic Effects in Cancer Treatments. J Microbiol Biotechnol 2022; 32:1086-1097. [PMID: 36116940 PMCID: PMC9628962 DOI: 10.4014/jmb.2208.08002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/15/2022]
Abstract
During the last decades, research and therapeutic methods in cancer treatment have been evolving. As the results, nowadays, cancer patients are receiving several types of treatments, ranging from chemotherapy and radiation therapy to surgery and immunotherapy. In fact, most cancer patients take a combination of current anti-cancer therapies to improve the efficacy of treatment. However, current strategies still cause some side effects to patients, such as pain and depression. Therefore, there is the need to discover better ways to eradicate cancer whilst minimizing side effects. Recently, immunotherapy, particularly immune checkpoint blockade, is rising as an effective anti-cancer treatment. Unlike chemotherapy or radiation therapy, immunotherapy has few side effects and a higher tumor cell removal efficacy depend on cellular immunological mechanisms. Moreover, recent studies suggest that tissue immune responses are regulated by their microbiome composition. Each tissue has their specific microenvironment, which makes their microbiome composition different, particularly in the context of different types of cancer, such as breast, colorectal, kidney, lung, and skin. Herein, we review the current understanding of the relationship of immune responses and tissue microbiome in cancer in both animal and human studies. Moreover, we discuss the cancermicrobiome-immune axis in the context of cancer development and treatment. Finally, we speculate on strategies to control tissue microbiome alterations that may synergistically affect the immune system and impact cancer treatment outcomes.
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Affiliation(s)
- Young Min Son
- Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Republic of Korea,Corresponding author Phone: +82-31-670-4792 E-mail:
| | - Jihwan Kim
- Department of Systems Biotechnology, Chung-Ang University, Anseong 17546, Republic of Korea
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10
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Tibbs E, Cao X. Murine myeloid derived suppressor cells possess a range of suppressive mechanisms-Granzyme B is not among them. Cancer Immunol Immunother 2022; 71:2255-2266. [PMID: 35129637 PMCID: PMC10693915 DOI: 10.1007/s00262-022-03162-z] [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: 07/02/2021] [Accepted: 01/21/2022] [Indexed: 10/19/2022]
Abstract
This paper addresses the controversy of Granzyme B (GzmB) expression by murine Myeloid Derived Suppressor Cells (MDSCs). MDSCs are a heterogenous immature myeloid population that are generated in chronic inflammatory pathologies for the purpose to suppress inflammatory responses. MDSCs express a multitude of factors to induce suppressive function such as PD-L1, reactive oxygen species (ROS), nitric oxide synthase (iNOS), and Arginase-1. Recently, Dufait et al. sought to demonstrate GzmB as an additional mechanism for suppression by MDSCs. They reported that murine MDSCs not only significantly express GzmB as well as Perforin (Prf1), but this expression is functionally important for tumor growth in vivo as well as tumor migration in vitro. We conducted experiments to address the same question but made confounding observations: MDSCs under stringent developmental process do not express GzmB. Our results show that not only GzmB protein is not produced at functional level, but the mRNA transcript is not detectable either. In fact, the GzmB protein found in the media of MDSC culture was due to T cells or natural killer cells contained in bone marrow and cultured alongside MDSCs. We strengthen this finding by genetically deleting GzmB from the myeloid lineage and measuring tumor burden compared to WT counterpart. Our results show no significant difference in tumor burden, suggesting that even if there is minor expression of GzmB, it is not produced at a functional amount to affect tumor growth. Therefore, this paper proposes alternative theories that align with the known understanding of GzmB expression and secretion.
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Affiliation(s)
- Ellis Tibbs
- School of Medicine, Department of Microbiology and Immunology, University of Maryland, Baltimore, USA
| | - Xuefang Cao
- School of Medicine, Department of Microbiology and Immunology, University of Maryland, Baltimore, USA.
- Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA.
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11
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Madeddu C, Sanna E, Nemolato S, Mulas O, Oppi S, Scartozzi M, La Nasa G, Maccio A. Pathogenic and Prognostic Roles of Paraneoplastic Leukocytosis in Cervical Cancer: Can Genomic-Based Targeted Therapies Have a Role? A Literature Review and an Emblematic Case Report. Diagnostics (Basel) 2022; 12:1910. [PMID: 36010260 PMCID: PMC9406983 DOI: 10.3390/diagnostics12081910] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/27/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor-associated leukocytosis has been associated with poor prognosis in cervical cancer. Leukemoid reaction (i.e., white blood cell count > 40,000/μL) is defined paraneoplastic (PLR) when it occurs in the presence of a cytokine-secreting tumor (CST) without neoplastic bone marrow infiltration. Cervical cancers displaying PLR represent a peculiar entity characterized by a rapidly progressive behavior typically associated with chemo-radioresistance. The present paper aims to review the literature about the pathogenetic mechanisms of PLR and its prognostic role in cervical cancer. Moreover, it reports the emblematic case of a patient with an advanced cervical cancer associated with PLR that was chemotherapy resistant. The patient underwent a palliative cytoreductive surgery of high complexity, obtaining a temporary regression of PLR. The tumor sample stained positive for G-CSF and IL-6, thus indicating a CST. Notably, the tumor genomic analysis revealed a PI3CKA mutation. Therefore, at the instrumental evidence of a rapidly progressive disease relapse, which was accompanied by reappearance of PLR, we started a targeted treatment with a selective PIK3 inhibitor alpesilib combined with the JAK1-2 inhibitor ruxolitinib. We achieved a relief of symptoms and leukocytosis; however, severe side effects necessitated the treatment suspension. In conclusion, as therapeutic strategies for cancer with PLR are scarcely reported in literature, our study could contribute to expand our understanding of the topic and provide a basis for further research.
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Affiliation(s)
- Clelia Madeddu
- Department of Medical Sciences and Public Health, University of Cagliari, 09100 Cagliari, Italy
| | - Elisabetta Sanna
- Department of Gynecologic Oncology, A. Businco Hospital, ARNAS G. Brotzu, 09100 Cagliari, Italy
| | - Sonia Nemolato
- Department of Pathology, ARNAS G. Brotzu, 09100 Cagliari, Italy
| | - Olga Mulas
- Hematology and Transplant Center, A. Businco Hospital, ARNAS G. Brotzu, 09100 Cagliari, Italy
| | - Sara Oppi
- Hematology and Transplant Center, A. Businco Hospital, ARNAS G. Brotzu, 09100 Cagliari, Italy
| | - Mario Scartozzi
- Department of Medical Sciences and Public Health, University of Cagliari, 09100 Cagliari, Italy
| | - Giorgio La Nasa
- Hematology and Transplant Center, A. Businco Hospital, ARNAS G. Brotzu, 09100 Cagliari, Italy
| | - Antonio Maccio
- Department of Gynecologic Oncology, A. Businco Hospital, ARNAS G. Brotzu, 09100 Cagliari, Italy
- Department of Surgical Sciences, University of Cagliari, 09100 Cagliari, Italy
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12
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Wang G, Wang J, Niu C, Zhao Y, Wu P. Neutrophils: New Critical Regulators of Glioma. Front Immunol 2022; 13:927233. [PMID: 35860278 PMCID: PMC9289230 DOI: 10.3389/fimmu.2022.927233] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/06/2022] [Indexed: 11/22/2022] Open
Abstract
In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are associated with malignant progression and immunosuppression in gliomas. However, recent studies have shown that neutrophils have an antitumour effect. In this review, we focus on the functional roles of neutrophils in the circulation and tumour sites in patients with glioma. The mechanisms of neutrophil recruitment, immunosuppression and the differentiation of neutrophils are discussed. Finally, the potential of neutrophils as clinical biomarkers and therapeutic targets is highlighted. This review can help us gain a deeper and systematic understanding of the role of neutrophils, and provide new insights for treatment in gliomas.
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Affiliation(s)
- Guanyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinpeng Wang
- Department of Urology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoshi Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, China
- Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, China
- Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, China
| | - Yan Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Pengfei Wu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, China
- Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, China
- Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
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13
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Ford JW, Gonzalez-Cotto M, MacFarlane AW, Peri S, Howard OMZ, Subleski JJ, Ruth KJ, Haseebuddin M, Al-Saleem T, Yang Y, Rayman P, Rini B, Linehan WM, Finke J, Weiss JM, Campbell KS, McVicar DW. Tumor-Infiltrating Myeloid Cells Co-Express TREM1 and TREM2 and Elevated TREM-1 Associates With Disease Progression in Renal Cell Carcinoma. Front Oncol 2022; 11:662723. [PMID: 35223446 PMCID: PMC8867210 DOI: 10.3389/fonc.2021.662723] [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: 02/08/2021] [Accepted: 09/27/2021] [Indexed: 12/22/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) contribute to cancer-related inflammation and tumor progression. While several myeloid molecules have been ascribed a regulatory function in these processes, the triggering receptors expressed on myeloid cells (TREMs) have emerged as potent modulators of the innate immune response. While various TREMs amplify inflammation, others dampen it and are emerging as important players in modulating tumor progression-for instance, soluble TREM-1 (sTREM-1), which is detected during inflammation, associates with disease progression, while TREM-2 expression is associated with tumor-promoting macrophages. We hypothesized that TREM-1 and TREM-2 might be co-expressed on tumor-infiltrating myeloid cells and that elevated sTREM-1 associates with disease outcomes, thus representing a possibility for mutual modulation in cancer. Using the 4T1 breast cancer model, we found TREM-1 and TREM-2 expression on MDSC and TAM and that sTREM-1 was elevated in tumor-bearing mice in multiple models and correlated with tumor volume. While TREM-1 engagement enhanced TNF, a TREM-2 ligand was detected on MDSC and TAM, suggesting that both TREM could be functional in the tumor setting. Similarly, we detected TREM-1 and Trem2 expression in myeloid cells in the RENCA model of renal cell carcinoma (RCC). We confirmed these findings in human disease by demonstrating the expression of TREM-1 on tumor-infiltrating myeloid cells from patients with RCC and finding that sTREM-1 was increased in patients with RCC. Finally, The Cancer Genome Atlas analysis shows that TREM1 expression in tumors correlates with poor outcomes in RCC. Taken together, our data suggest that manipulation of the TREM-1/TREM-2 balance in tumors may be a novel means to modulate tumor-infiltrating myeloid cell phenotype and function.
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Affiliation(s)
- Jill W Ford
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Marieli Gonzalez-Cotto
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Alexander W MacFarlane
- Blood Cell Development and Function Program, Institute for Cancer Research, Philadelphia, PA, United States
| | - Suraj Peri
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - O M Zack Howard
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Jeffrey J Subleski
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Karen J Ruth
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Mohammed Haseebuddin
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Tahseen Al-Saleem
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Youfeng Yang
- Urologic Oncology Branch, National Cancer Institute (NCI), Bethesda, MD, United States
| | - Pat Rayman
- Cleveland Clinic, Department of Immunology, Lerner Research Institute, Cleveland, OH, United States
| | - Brian Rini
- Cleveland Clinic, Department of Solid Tumor Oncology, Cleveland, OH, United States
| | - W Marston Linehan
- Urologic Oncology Branch, National Cancer Institute (NCI), Bethesda, MD, United States
| | - James Finke
- Cleveland Clinic, Department of Immunology, Lerner Research Institute, Cleveland, OH, United States
| | - Jonathan M Weiss
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
| | - Kerry S Campbell
- Blood Cell Development and Function Program, Institute for Cancer Research, Philadelphia, PA, United States
| | - Daniel W McVicar
- Laboratory of Cancer Immunometabolism, National Cancer Institute (NCI), Frederick, MD, United States
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14
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Soler DC, Kerstetter-Fogle A, Young AB, Rayman P, Finke JH, Debanne SM, Cooper KD, Barnholtz-Sloan J, Sloan AE, McCormick TS. Healthy myeloid-derived suppressor cells express the surface ectoenzyme Vanin-2 (VNN2). Mol Immunol 2022; 142:1-10. [PMID: 34953280 PMCID: PMC8800381 DOI: 10.1016/j.molimm.2021.12.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/18/2021] [Accepted: 12/09/2021] [Indexed: 02/03/2023]
Abstract
Study of human monocytic Myeloid-Derived Suppressor cells Mo-MDSC (CD14+ HLA-DRneg/low) has been hampered by the lack of positive cell-surface markers. In order to identify positive markers for Mo-MDSC, we performed microarray analysis comparing Mo-MDSC cells from healthy subjects versus CD14+ HLA-DRhigh monocytes. We have identified the surface ectoenzyme Vanin-2(VNN2) protein as a novel biomarker highly-enriched in healthy subjects Mo-MDSC. Indeed, healthy subjects Mo-MDSC cells expressed 68 % VNN2, whereas only 9% VNN2 expression was observed on CD14+ HLA-DRhigh cells (n = 4 p < 0.01). The top 10 percent positive VNN2 monocytes expressed CD33 and CD11b while being negative for HLA-DR, CD3, CD15, CD19 and CD56, consistent with a Mo-MDSC phenotype. CD14+VNN2high monocytes were able to inhibit CD8 T cell proliferation comparably to traditional Mo-MDSC at 51 % and 48 % respectively. However, VNN2 expression on CD14+ monocytes from glioma patients was inversely correlated to their grade. CD14+VNN2high monocytes thus appear to mark a monocytic population similar to Mo-MDSC only in healthy subjects, which may be useful for tumor diagnoses.
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Affiliation(s)
- David C. Soler
- The Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH 44195.,Brain Tumor and Neuro-Oncology Center, and the Center of Excellence for Translational Neuro-Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195.,University Hospitals-Seidman Center and the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Amber Kerstetter-Fogle
- The Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH 44195.,Brain Tumor and Neuro-Oncology Center, and the Center of Excellence for Translational Neuro-Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195.,University Hospitals-Seidman Center and the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Andrew B. Young
- Department of Dermatology, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA.,The Murdough Family Center for Psoriasis, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA
| | - Pat Rayman
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - James H. Finke
- Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Sarah M. Debanne
- Epidemiology and Biostatistics, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA
| | - Kevin D. Cooper
- Department of Dermatology, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA.,The Murdough Family Center for Psoriasis, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA
| | - Jill Barnholtz-Sloan
- The Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH 44195.,Brain Tumor and Neuro-Oncology Center, and the Center of Excellence for Translational Neuro-Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195.,University Hospitals-Seidman Center and the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195.,Epidemiology and Biostatistics, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA
| | - Andrew E. Sloan
- The Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH 44195.,Brain Tumor and Neuro-Oncology Center, and the Center of Excellence for Translational Neuro-Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195.,University Hospitals-Seidman Center and the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Thomas S. McCormick
- Department of Dermatology, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA.,The Murdough Family Center for Psoriasis, University Hospitals-Cleveland Medical Center and the Case Western University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106 USA
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15
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Detection of Circulating and Tissue Myeloid-Derived Suppressor Cells (MDSC) by Flow Cytometry. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2422:247-261. [PMID: 34859411 DOI: 10.1007/978-1-0716-1948-3_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Flow cytometry allows the multiparameter analysis of heterogeneous cell populations and is an essential tool for detecting and characterizing different cell populations from peripheral blood and dissociated tissues. Myeloid-derived suppressor cells (MDSC) are a heterogeneous and plastic group of myeloid precursors with immune-suppressive capacity, which are a characteristic feature of chronic inflammation, such as cancer. The optimal measurement of MDSC levels could be used as a biomarker for clinicians for prognosis and/or management and for researchers to track and understand the role of MDSC in different pathological diseases.The criteria for defining MDSC include phenotypic surface markers, but ideally should also include the functional immunosuppressive effect on T cells, and, if possible, assessing the main biochemical and molecular features. Two major functional mechanisms to suppress T cell responses are the production of arginase-1 and reactive oxygen species (ROS) molecules. Here is presented a nine-parameter seven-color flow cytometric assay to identify and quantify MDSC from both peripheral blood mononuclear cells (PBMC) and dissociated tissue (e.g., tumor) by using fluorescence-tagged antibodies against surface markers. Also, the intracellular levels of arginase-1 and superoxide (O2-) content were performed to potentially distinguish their functional status.
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16
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Budhwar S, Verma R, Verma P, Bala R, Rai S, Singh K. Estradiol correlates with the accumulation of Monocytic Myeloid-Derived Suppressor Cells in Pre-term birth: A possible explanation of immune suppression in pre-term babies. J Reprod Immunol 2021; 147:103350. [PMID: 34293589 DOI: 10.1016/j.jri.2021.103350] [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: 04/02/2021] [Revised: 06/27/2021] [Accepted: 07/04/2021] [Indexed: 10/20/2022]
Abstract
Synergistic interplay of immune endocrine interaction is prerequisite for an effective maternal fetal tolerance. Pre-term birth (PTB) may be a consequence of altered immune-endocrine crosstalk during third trimester resulting in early breakdown of this tolerance. Myeloid derived suppressor cells (MDSCs), a heterogenous population of immature immune cells are increased in pregnant women and healthy newborns, but their role in PTB still remains obscure. We now report that granulocytic MDSCs (G-MDSCs) is decreased in women delivering prematurely, suggesting their potential role in maintaining maternal fetal tolerance. Interestingly, in contrast statistically significant increase in MDSCs and monocytic MDSCs (M-MDSCs) along with positive correlation with cord serum estradiol (E2), and overexpressed ER-α in placental tissue suggested E2 mediated accumulation of M-MDSCs in PTB babies. MDSCs mediated immune suppression is accompanied with subsequent decline in total T cells and its subtypes: Th and Tc in PTB babies, which signifies their potential contribution towards the impaired immune system of PTB babies.
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Affiliation(s)
- Snehil Budhwar
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Rachna Verma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Priyanka Verma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Renu Bala
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Sangeeta Rai
- Department of Obstetrics and Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Kiran Singh
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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17
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Lei MML, Lee TKW. Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers. Front Cell Dev Biol 2021; 9:692940. [PMID: 34235155 PMCID: PMC8257022 DOI: 10.3389/fcell.2021.692940] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) are subpopulations of undifferentiated cancer cells within the tumor bulk that are responsible for tumor initiation, recurrence and therapeutic resistance. The enhanced ability of CSCs to give rise to new tumors suggests potential roles of these cells in the evasion of immune surveillance. A growing body of evidence has described the interplay between CSCs and immune cells within the tumor microenvironment (TME). Recent data have shown the pivotal role of some major immune cells in driving the expansion of CSCs, which concurrently elicit evasion of the detection and destruction of various immune cells through a number of distinct mechanisms. Here, we will discuss the role of immune cells in driving the stemness of cancer cells and provide evidence of how CSCs evade immune surveillance by exerting their effects on tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), T-regulatory (Treg) cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes (TILs). The knowledge gained from the interaction between CSCs and various immune cells will provide insight into the mechanisms by which tumors evade immune surveillance. In conclusion, CSC-targeted immunotherapy emerges as a novel immunotherapy strategy against cancer by disrupting the interaction between immune cells and CSCs in the TME.
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Affiliation(s)
- Martina Mang Leng Lei
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong.,State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Kowloon, Hong Kong
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18
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Sanchez-Pino MD, Gilmore LA, Ochoa AC, Brown JC. Obesity-Associated Myeloid Immunosuppressive Cells, Key Players in Cancer Risk and Response to Immunotherapy. Obesity (Silver Spring) 2021; 29:944-953. [PMID: 33616242 PMCID: PMC8154641 DOI: 10.1002/oby.23108] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 12/16/2022]
Abstract
Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.
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Affiliation(s)
- Maria Dulfary Sanchez-Pino
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA
- Department of Genetics, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA
| | | | - Augusto C. Ochoa
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA
- Department of Pediatrics, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA
| | - Justin C. Brown
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA
- Department of Genetics, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA
- LSU Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
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19
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Qayyum A, Bhosale P, Aslam R, Avritscher R, Ma J, Pagel MD, Sun J, Mohamed Y, Rashid A, Beretta L, Kaseb AO. Effect of sarcopenia on systemic targeted therapy response in patients with advanced hepatocellular carcinoma. Abdom Radiol (NY) 2021; 46:1008-1015. [PMID: 32974761 PMCID: PMC8191337 DOI: 10.1007/s00261-020-02751-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/27/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Sarcopenia is an independent prognostic indicator for hepatocellular carcinoma (HCC). Our objective was to determine the effect of sarcopenia on response to systemic targeted therapy in patients with advanced HCC. MATERIALS AND METHODS This was a retrospective, Institutional Review Board approved study of 36 patients on systemic targeted therapy with immune checkpoint blockade (n = 25) or tyrosine kinase inhibitor (n = 11) for biopsy-proven advanced HCC. Skeletal muscle index (SMI) was calculated from erector spinae muscle area (SMA) at the level of T12 on pretreatment CT: [SMI = SMA (cm2)/height (m2)]. SMI was compared to treatment response defined as overall survival ≥ 1 year (nonsurgical patients) or > 50% HCC necrosis (surgical patients). Receiver operating characteristic curve and area under the curve was used for analysis with p < 0.05 for statistical significance. RESULTS Median age of men and women was 66.5 years (range 32-83) and 70 years (range 54-78), respectively. Liver disease etiology was nonalcoholic steatohepatitis (n = 9), hepatitis C (n = 10), hepatitis B (n = 5), alcohol (n = 3) and unknown (n = 9). Mean (± SD) height and SMI for men were 1.7 m (± 0.1) and 11.4 (± 3.6); values for women were 1.7 m (± 0.1) and 8.2 (± 1.9). Treatment was withdrawn in five patients due to treatment intolerance. Response occurred in 10/31 (32.3%) patients (23 men, 8 women). T12SMI correlated with treatment response using a threshold of 7.21-8.23 for women (AUC = 1; p = 0.037), and 11.47 for men (AUC = 0.83; p = 0.015); correlation was increased for men ≥ 60 years, (AUC = 0.87; p = 0.023). CONCLUSION Sarcopenia was associated with reduced survival and HCC necrosis in patients treated with systemic targeted therapy. CLINICAL RELEVANCE Sarcopenia may help in predicting outcomes to targeted therapy in advanced HCC.
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Affiliation(s)
- Aliya Qayyum
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Unit 1473, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
| | - Priya Bhosale
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Unit 1473, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Rizwan Aslam
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Unit 1473, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Rony Avritscher
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Jingfei Ma
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Mark D Pagel
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Jia Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Yehia Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
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20
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Danilin S, Merkel AR, Johnson JR, Johnson RW, Edwards JR, Sterling JA. Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction. Oncoimmunology 2021; 1:1484-1494. [PMID: 23264895 PMCID: PMC3525604 DOI: 10.4161/onci.21990] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs), identified as Gr1+CD11b+ cells in mice, expand during cancer and promote tumor growth, recurrence and burden. However, little is known about their role in bone metastases. We hypothesized that MDSCs may contribute to tumor-induced bone disease, and inoculated breast cancer cells into the left cardiac ventricle of nude mice. Disease progression was monitored weekly by X-ray and fluorescence imaging and MDSCs expansion by fluorescence-activated cell sorting. To explore the contribution of MDSCs to bone metastasis, we co-injected mice with tumor cells or PBS into the left cardiac ventricle and Gr1+CD11b+ cells isolated from healthy or tumor-bearing mice into the left tibia. MDSCs didn’t induce bone resorption in normal mice, but increased resorption and tumor burden significantly in tumor-bearing mice. In vitro experiments showed that Gr1+CD11b+ cells isolated from normal and tumor-bearing mice differentiate into osteoclasts when cultured with RANK ligand and macrophage colony-stimulating factor, and that MDSCs from tumor-bearing mice upregulate parathyroid hormone-related protein (PTHrP) mRNA levels in cancer cells. PTHrP upregulation is likely due to the 2-fold increase in transforming growth factor β expression that we observed in MDSCs isolated from tumor-bearing mice. Importantly, using MDSCs isolated from GFP-expressing animals, we found that MDSCs differentiate into osteoclast-like cells in tumor-bearing mice as evidenced by the presence of GFP+TRAP+ cells. These results demonstrate that MDSCs expand in breast cancer bone metastases and induce bone destruction. Furthermore, our data strongly suggest that MDSCs are able to differentiate into osteoclasts in vivo and that this is stimulated in the presence of tumors.
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Affiliation(s)
- Sabrina Danilin
- Division of Clinical Pharmacology; Department of Medicine; Vanderbilt Center for Bone Biology; Nashville, TN USA ; INSERM U682; Section of Renal Cancer and Renal Physiopathology; University of Strasbourg; School of Medicine; Strasbourg, France
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21
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Obermajer N, Kalinski P. Key role of the positive feedback between PGE(2) and COX2 in the biology of myeloid-derived suppressor cells. Oncoimmunology 2021; 1:762-764. [PMID: 22934275 PMCID: PMC3429587 DOI: 10.4161/onci.19681] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
PGE2 is the key factor needed for MDSCs development, accumulation and functional stability. PGE2 initiates an EP2/EP4-mediated positive feedback between COX2 and PGE2 in monocytic precursors, redirecting dendritic cell differentiation to MDSCs. COX2- or EP2/EP4- blockade abrogates MDSC functions and their CXCR4-CXCL12-mediated attraction to cancer environment, providing convenient immunotherapeutic targets.
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Affiliation(s)
- Nataŝa Obermajer
- Department of Surgery; University of Pittsburgh; Pittsburgh, PA USA
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22
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Farshidpour M, Ahmed M, Junna S, Merchant JL. Myeloid-derived suppressor cells in gastrointestinal cancers: A systemic review. World J Gastrointest Oncol 2021; 13:1-11. [PMID: 33510845 PMCID: PMC7805271 DOI: 10.4251/wjgo.v13.i1.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/01/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers are one of the most common malignancies worldwide, with high rates of morbidity and mortality. Myeloid-derived suppressor cells (MDSCs) are major components of the tumor microenvironment (TME). MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis. Moreover, in patients with GI malignancies, MDSCs can lead to the suppression of T cells and natural killer cells. Accordingly, a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.
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Affiliation(s)
- Maham Farshidpour
- Inpatient Medicine, Banner University of Medical Center, Tucson, AZ 85724, United States
| | - Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Shilpa Junna
- Division of Gastroenterology and Hepatology, Banner University of Medical Center, Tucson, AZ 85724, United States
| | - Juanita L Merchant
- Division of Gastroenterology and Hepatology, Banner University of Medical Center, Tucson, AZ 85724, United States
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23
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Chen H, Li M, Guo Y, Zhong Y, He Z, Xu Y, Zou J. Immune response in glioma's microenvironment. Innov Surg Sci 2021; 5:20190001. [PMID: 33511267 PMCID: PMC7810204 DOI: 10.1515/iss-2019-0001] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 10/30/2020] [Indexed: 01/09/2023] Open
Abstract
Objectives Glioma is the most common tumor of the central nervous system. In this review, we outline the immunobiological factors that interact with glioma cells and tumor microenvironment (TME), providing more potential targets for clinical inhibition of glioma development and more directions for glioma treatment. Content Recent studies have shown that glioma cells secrete a variety of immune regulatory factors and interact with immune cells such as microglial cells, peripheral macrophages, myeloid-derived suppressor cells (MDSCs), and T lymphocytes in the TME. In particular, microglia plays a key role in promoting glioma growth. Infiltrating immune cells induce local production of cytokines, chemokines and growth factors. Further leads to immune escape of malignant gliomas. Summary and Outlook The complex interaction of tumor cells with the TME has largely contributed to tumor heterogeneity and poor prognosis. We review the immunobiological factors, immune cells and current immunotherapy of gliomas, provide experimental evidence for future research and treatment of gliomas.
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Affiliation(s)
- Houminji Chen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China.,The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Ming Li
- Department of Neurosurgery, Henan Provical People's Hospital, Zhengzhou, P. R. China
| | - Yanwu Guo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Yongsheng Zhong
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Zhuoyi He
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Yuting Xu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Junjie Zou
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, P. R. China
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24
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Jackson K, Milner RJ, Doty A, Hutchison S, Cortes-Hinojosa G, Riva A, Sahay B, Lejeune A, Bechtel S. Analysis of canine myeloid-derived suppressor cells (MDSCs) utilizing fluorescence-activated cell sorting, RNA protection mediums to yield quality RNA for single-cell RNA sequencing. Vet Immunol Immunopathol 2020; 231:110144. [PMID: 33278779 DOI: 10.1016/j.vetimm.2020.110144] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 10/15/2020] [Accepted: 10/27/2020] [Indexed: 12/20/2022]
Abstract
Fluorescence-activated cell sorting (FACS) is a branch of flow cytometry that allows for the isolation of specific cell populations that can then be further analyzed by single-cell RNA sequencing (scRNA-seq). When utilizing FACS for population isolation prior to sequencing, it is essential to consider the protection of RNA from RNase activity, environmental conditions, and the sorting efficiency to ensure optimum sample quality. This study aimed to optimize a previously published MDSC flow cytometry strategy to FACS sort canine Myeloid-Derived Suppressor Cells (MDSC) with various permutations of RNAlater ™ and RiboLock™ before and after FACS sorting. Concentrations of RNAlater™ greater than 2 % applied before flow analysis affected cell survival and fluorescence, whereas concentrations ≤ 2 % and time ≤ 4 h had little to no effect on cells. To shorten the procedural time and to enhance the sorting of rare populations, we used a primary PE-conjugated CD11b antibody and magnetic column. The combination of RiboLock™ pre- and post-sorting for FACS provided the best quality RNA as determined by the RNA integrity number (RIN ≥ 7) for scRNA-seq in a normal and dog and a dog with untreated oral melanoma dog. As proof of principle, we sequenced two samples, one from a normal dog another from a dog with untreated oral melanoma. Applying scRNA-Seq analysis using the 10X Genomic platform, we identified 6 clusters in the Seurat paired analysis of MDSC sorted samples. Two clusters, with the majority of the cells coming from the melanoma sample, had genes that were upregulated (> log2); these included MMP9, MMP1, HPGD, CPA3, and GATA3 and CYBB, CSTB, COX2, ATP6, and COX 17 for cluster 5 and 6 respectively. All genes have known associations with MDSCs. Further characterization using pathway analysis tools was not attempted due to the lower number of cells sequenced in the normal sample. The benefit deriving from the results of the study helped to gain data consistency when working with cells prone to RNase activity, and the scRNA-seq provided data showing transcriptional heterogeneity in MDSC populations and potentially identifying previously unreported or rare cell populations.
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Affiliation(s)
- K Jackson
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, United States
| | - R J Milner
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, United States.
| | - A Doty
- Flow Cytometry and Imaging Core Lab, Interdisciplinary Center for Biotechnology Research, University of Florida, United States
| | - S Hutchison
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, United States
| | - G Cortes-Hinojosa
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, United States
| | - A Riva
- Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, United States
| | - B Sahay
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, United States
| | - A Lejeune
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, United States
| | - S Bechtel
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, United States
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25
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Han X, Luan T, Sun Y, Yan W, Wang D, Zeng X. MicroRNA 449c Mediates the Generation of Monocytic Myeloid-Derived Suppressor Cells by Targeting STAT6. Mol Cells 2020; 43:793-803. [PMID: 32863280 PMCID: PMC7528684 DOI: 10.14348/molcells.2020.2307] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 08/10/2020] [Accepted: 08/10/2020] [Indexed: 12/21/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) promote tumour progression by contributing to angiogenesis, immunosuppression, and immunotherapy resistance. Although recent studies have shown that microRNAs (miRNAs) can promote the expansion of MDSCs in the tumour environment, the mechanisms involved in this process are largely unknown. Here, we report that microRNA 449c (miR-449c) expression was upregulated in myeloid progenitor cells upon activation of C-X-C motif chemokine receptor 2 (CXCR2) under tumour conditions. MiR-449c upregulation increased the generation of monocytic MDSCs (mo-MDSCs). The increased expression of miR-449c could target STAT6 mRNA in myeloid progenitor cells to shift the differentiation balance of myeloid progenitor cells and lead to an enhancement of the mo-MDSCs population in the tumour environment. Thus, our results demonstrate that the miR-449c/STAT6 axis is involved in the expansion of mo-MDSCs from myeloid progenitor cells upon activation of CXCR2, and thus, inhibition of miR-449c/STAT6 signalling may help to attenuate tumour progression.
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Affiliation(s)
- Xiaoqing Han
- The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Tao Luan
- The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Yingying Sun
- The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Wenyi Yan
- The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Dake Wang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Xianlu Zeng
- The Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun 130024, China
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26
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Hahm ER, Kim SH, Singh KB, Singh K, Singh SV. A Comprehensive Review and Perspective on Anticancer Mechanisms of Withaferin A in Breast Cancer. Cancer Prev Res (Phila) 2020; 13:721-734. [PMID: 32727824 DOI: 10.1158/1940-6207.capr-20-0259] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/23/2020] [Accepted: 07/22/2020] [Indexed: 01/07/2023]
Abstract
Withaferin A (hereafter abbreviated as WA) is a promising anticancer steroidal lactone abundant in a medicinal plant (Withania somnifera) native to Asia. The root/leaf extract of Withania somnifera, which belongs to the Solanaceae family, continues to be included in the Ayurvedic medicine formulations of alternative medicine practice. Numerous chemicals are detectable in the root/leaf extract of Withania somnifera [e.g., withanolides (WA, withanone, withanolide A, etc.), alkaloids, sitoindosides, etc.], but the anticancer effect of this medicinal plant is largely attributed to WA. Anticancer effect of WA was initially reported in the early 70s in the Ehrlich ascites tumor cell model in vitro Since then, numerous preclinical studies have been performed using cellular and animal models of different cancers including breast cancer to determine cancer therapeutic and chemopreventive effects of WA. Chemoprevention, a word first introduced by Dr. Michael B. Sporn, was intended to impede, arrest, or reverse carcinogenesis at its earliest stages with pharmacologic agents. This review succinctly summarizes the published findings on anticancer pharmacology of WA in breast cancer focusing on pharmacokinetic behavior, in vivo efficacy data in preclinical models in a therapeutic and chemoprevention settings, and its known effects on cancer-relevant cellular processes (e.g., growth arrest, apoptosis induction, autophagy, metabolic adaptation, immune function, etc.) and molecular targets (e.g., suppression of oncogenes such as estrogen receptor-α, STAT3, etc.). Potential gaps in knowledge as well as future research directions essential for clinical development of WA for chemoprevention and/or treatment of breast cancer are also discussed.
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Affiliation(s)
- Eun-Ryeong Hahm
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Su-Hyeong Kim
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Krishna B Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kamayani Singh
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shivendra V Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. .,UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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27
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Cheng YQ, Wang SB, Liu JH, Jin L, Liu Y, Li CY, Su YR, Liu YR, Sang X, Wan Q, Liu C, Yang L, Wang ZC. Modifying the tumour microenvironment and reverting tumour cells: New strategies for treating malignant tumours. Cell Prolif 2020; 53:e12865. [PMID: 32588948 PMCID: PMC7445401 DOI: 10.1111/cpr.12865] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti‐tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti‐tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME—such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell‐based microenvironment therapies—to provide novel ideas for producing breakthroughs in tumour therapy strategies.
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Affiliation(s)
- Ya Qi Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shou Bi Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jia Hui Liu
- Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, China
| | - Lin Jin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ying Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chao Yang Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ya Ru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yu Run Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuan Sang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qi Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chang Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Liu Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhi Chong Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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28
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Kelly-Scumpia KM, Choi A, Shirazi R, Bersabe H, Park E, Scumpia PO, Ochoa MT, Yu J, Ma F, Pellegrini M, Modlin RL. ER Stress Regulates Immunosuppressive Function of Myeloid Derived Suppressor Cells in Leprosy that Can Be Overcome in the Presence of IFN-γ. iScience 2020; 23:101050. [PMID: 32339990 PMCID: PMC7190750 DOI: 10.1016/j.isci.2020.101050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/27/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
Myeloid derived suppressor cells (MDSCs) are a population of immature myeloid cells that suppress adaptive immune function, yet the factors that regulate their suppressive function in patients with infection remain unclear. We studied MDSCs in patients with leprosy, a disease caused by Mycobacterium leprae, where clinical manifestations present on a spectrum that correlate with immunity to the pathogen. We found that HLA-DR-CD33+CD15+ MDSCs were increased in blood from patients with disseminated/progressive lepromatous leprosy and possessed T cell-suppressive activity as compared with self-limiting tuberculoid leprosy. Mechanistically, we found ER stress played a critical role in regulating the T cell suppressive activity in these MDSCs. Furthermore, ER stress augmented IL-10 production, contributing to MDSC activity, whereas IFN-γ allowed T cells to overcome MDSC suppressive activity. These studies highlight a regulatory mechanism that links ER stress to IL-10 in mediating MDSC suppressive function in human infectious disease.
Cells with an MDSC phenotype are increased in blood and skin of patients with leprosy Only MDSCs from patients with leprosy with disseminated infection suppress T cell function MDSC function is dependent on increased ER stress and IL-10 production MDSC function can be reversed in the presence of IFN-γ
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Affiliation(s)
| | - Aaron Choi
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Roksana Shirazi
- Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA
| | - Hannah Bersabe
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Esther Park
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Philip O Scumpia
- Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA
| | - Maria T Ochoa
- Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Jing Yu
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Feiyang Ma
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Robert L Modlin
- Division of Dermatology, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA
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29
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Wu G, Huang F, Chen Y, Zhuang Y, Huang Y, Xie Y. High Levels of BMP2 Promote Liver Cancer Growth via the Activation of Myeloid-Derived Suppressor Cells. Front Oncol 2020; 10:194. [PMID: 32195173 PMCID: PMC7064622 DOI: 10.3389/fonc.2020.00194] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/05/2020] [Indexed: 12/16/2022] Open
Abstract
Bone morphogenetic protein 2 (BMP2) signaling had significant roles in diverse pathological processes, such as cancer. Nevertheless, the interaction between BMP2 and carcinoma development remained largely unknown. In particular, the roles that BMP2 play in the development of liver cancer remained controversial, and mechanisms were unclear. BMP2 with strong osteogenic potential had been manufactured into various bone materials. However, cancer risk concerns were raised in recent years. Thus, we focused on analyzing the effects of exogenous BMP2 on the growth of liver cancer and the detailed mechanisms. We found that both intravenous injection of rhBMP2 and in vivo implantation of rhBMP2 materials could lead to the expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood and subsequently enhanced the infiltration of MDSCs into tumor in vivo. Furthermore, BMP2 signaling-activated MDSCs could secrete IL6 to enhance cell proliferation of liver cancer cells in vitro and facilitate liver cancer growth in vivo. Our study indicated that increased concentration of BMP2 within the peripheral blood could enhance liver cancer growth via the activation of MDSCs. In this study, the roles that BMP2 played in liver cancer growth were further confirmed and the detailed mechanisms about how BMP2 enhanced liver cancer growth were also elucidated.
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Affiliation(s)
- Gui Wu
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Fei Huang
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yaoqing Chen
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yuehong Zhuang
- Department of Human Anatomy and Embryology, Institute of Neuroscientific Study, Fujian Medical University, Fuzhou, China
| | - Yunpeng Huang
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yun Xie
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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30
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Bosiljcic M, Cederberg RA, Hamilton MJ, LePard NE, Harbourne BT, Collier JL, Halvorsen EC, Shi R, Franks SE, Kim AY, Banáth JP, Hamer M, Rossi FM, Bennewith KL. Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs. Breast Cancer Res 2019; 21:103. [PMID: 31488209 PMCID: PMC6727565 DOI: 10.1186/s13058-019-1189-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 08/16/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Solid tumors produce proteins that can induce the accumulation of bone marrow-derived cells in various tissues, and these cells can enhance metastatic tumor growth by several mechanisms. 4T1 murine mammary tumors are known to produce granulocyte colony-stimulating factor (G-CSF) and increase the numbers of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) in tissues such as the spleen and lungs of tumor-bearing mice. While surgical resection of primary tumors decreases MDSC levels in the spleen, the longevity and impact of MDSCs and other immune cells in the lungs after tumor resection have been less studied. METHODS We used mass cytometry time of flight (CyTOF) and flow cytometry to quantify MDSCs in the spleen, peripheral blood, and lungs of mice bearing orthotopic murine mammary tumors. We also tested the effect of primary tumor resection and/or gemcitabine treatment on the levels of MDSCs, other immune suppressor and effector cells, and metastatic tumor cells in the lungs. RESULTS We have found that, similar to mice with 4T1 tumors, mice bearing metastatic 4T07 tumors also exhibit accumulation of CD11b+Gr1+ MDSCs in the spleen and lungs, while tissues of mice with non-metastatic 67NR tumors do not contain MDSCs. Mice with orthotopically implanted 4T1 tumors have increased granulocytic (G-) MDSCs, monocytic (M-) MDSCs, macrophages, eosinophils, and NK cells in the lungs. Resection of primary 4T1 tumors decreases G-MDSCs, M-MDSCs, and macrophages in the lungs within 48 h, but significant numbers of functional immunosuppressive G-MDSCs persist in the lungs for 2 weeks after tumor resection, indicative of an environment that can promote metastatic tumor growth. The chemotherapeutic agent gemcitabine depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils in the lungs of 4T1 tumor-bearing mice, and we found that treating mice with gemcitabine after primary tumor resection decreases residual G-MDSCs in the lungs and decreases subsequent metastatic growth. CONCLUSIONS Our data support the development of therapeutic strategies to target MDSCs and to monitor MDSC levels before and after primary tumor resection to enhance the effectiveness of immune-based therapies and improve the treatment of metastatic breast cancer in the clinic.
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Affiliation(s)
- Momir Bosiljcic
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.,Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Rachel A Cederberg
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.,Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Melisa J Hamilton
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | - Nancy E LePard
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | - Bryant T Harbourne
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.,Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jenna L Collier
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | - Elizabeth C Halvorsen
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.,Interdisciplinary Oncology Program, University of British Columbia, Vancouver, British Columbia, Canada
| | - Rocky Shi
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | - S Elizabeth Franks
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | - Ada Y Kim
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada.,Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Judit P Banáth
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
| | - Mark Hamer
- Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Fabio M Rossi
- Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Kevin L Bennewith
- Integrative Oncology Department, BC Cancer Research Centre, Room 10-108, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada. .,Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. .,Interdisciplinary Oncology Program, University of British Columbia, Vancouver, British Columbia, Canada.
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31
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Abstract
Circulating tumor cells (CTCs) play a central role in tumor dissemination and metastases, which are ultimately responsible for most cancer deaths. Technologies that allow for identification and enumeration of rare CTC from cancer patients' blood have already established CTC as an important clinical biomarker for cancer diagnosis and prognosis. Indeed, current efforts to robustly characterize CTC as well as the associated cells of the tumor microenvironment such as circulating cancer associated fibroblasts (cCAF), are poised to unmask key insights into the metastatic process. Ultimately, the clinical utility of CTC will be fully realized once CTC can be reliably cultured and proliferated as a biospecimen for precision management of cancer patients, and for discovery of novel therapeutics. In this review, we highlight the latest CTC capture and analyses technologies, and discuss in vitro strategies for culturing and propagating CTC.
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Affiliation(s)
- Ashutosh Agarwal
- Assistant Professor, Department of Biomedical Engineering, Department of Pathology & Laboratory Medicine, University of Miami
| | - Marija Balic
- Associate Professor, Division of Oncology, Department of Internal Medicine, Research Unit Circulating Tumor Cells and Cancer Stem Cells, Medical University of Graz, Austria
| | - Dorraya El-Ashry
- Associate Professor, Department of Laboratory Medicine and Pathology, University of Minnesota
| | - Richard J. Cote
- Professor and Joseph R. Coulter Jr. Chair, Department of Pathology & Laboratory Medicine, Director, John T. Macdonald Foundation Biomedical Nanotechnology Institute (BioNIUM), University of Miami Miller School of Medicine
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32
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Ochando J, Conde P, Utrero-Rico A, Paz-Artal E. Tolerogenic Role of Myeloid Suppressor Cells in Organ Transplantation. Front Immunol 2019; 10:374. [PMID: 30894860 PMCID: PMC6414442 DOI: 10.3389/fimmu.2019.00374] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/14/2019] [Indexed: 01/10/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells of myeloid origin with a specific immune inhibitory function that negatively regulates the adaptive immune response. Since MDSC participate in the promotion of tolerance in the context of organ transplantation, therapeutic strategies that regulate the induction and development of MDSC have been the center of scientist attention. Here we review literature regarding induction of MDSC with demonstrated suppressive function among different types of allografts and their mechanism of action. While manipulation of MDSC represents a potential therapeutic approach for the promotion of donor specific tolerance in solid organ transplantation, further characterization of their specific phenotype, which distinguishes MDSC from non-suppressive myeloid cells, and detailed evaluation of the inhibitory mechanism that determines their suppressive function, is necessary for the realistic application of MDSC as biomarkers in health and disease and their potential use as immune cell therapy in organ transplantation.
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Affiliation(s)
- Jordi Ochando
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Conde
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Alberto Utrero-Rico
- Grupo de Inmunodeficiencias e Inmunología del Trasplante, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Estela Paz-Artal
- Grupo de Inmunodeficiencias e Inmunología del Trasplante, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.,School of Medicine, Complutense University, Madrid, Spain
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33
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Gonzalez-Avila G, Sommer B, Mendoza-Posada DA, Ramos C, Garcia-Hernandez AA, Falfan-Valencia R. Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit Rev Oncol Hematol 2019; 137:57-83. [PMID: 31014516 DOI: 10.1016/j.critrevonc.2019.02.010] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 02/11/2019] [Accepted: 02/24/2019] [Indexed: 12/13/2022] Open
Abstract
Matrix metalloproteinases (MMPs) participate from the initial phases of cancer onset to the settlement of a metastatic niche in a second organ. Their role in cancer progression is related to their involvement in the extracellular matrix (ECM) degradation and in the regulation and processing of adhesion and cytoskeletal proteins, growth factors, chemokines and cytokines. MMPs participation in cancer progression makes them an attractive target for cancer therapy. MMPs have also been used for theranostic purposes in the detection of primary tumor and metastatic tissue in which a particular MMP is overexpressed, to follow up on therapy responses, and in the activation of cancer cytotoxic pro-drugs as part of nano-delivery-systems that increase drug concentration in a specific tumor target. Herein, we review MMPs molecular characteristics, their synthesis regulation and enzymatic activity, their participation in the metastatic process, and how their functions have been used to improve cancer treatment.
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Affiliation(s)
- Georgina Gonzalez-Avila
- Laboratorio Oncología Biomédica, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico.
| | - Bettina Sommer
- Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
| | | | - Carlos Ramos
- Laboratorio de Biología Celular, Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
| | - A Armando Garcia-Hernandez
- Laboratorio Oncología Biomédica, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
| | - Ramces Falfan-Valencia
- Laboratorio de HLA, Departamento de Inmunogenética y Alergia, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
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Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy. Front Immunol 2019; 9:3176. [PMID: 30719026 PMCID: PMC6348254 DOI: 10.3389/fimmu.2018.03176] [Citation(s) in RCA: 268] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 12/24/2018] [Indexed: 12/13/2022] Open
Abstract
Dendritic cells (DC) are professional antigen presenting cells, uniquely able to induce naïve T cell activation and effector differentiation. They are, likewise, involved in the induction and maintenance of immune tolerance in homeostatic conditions. Their phenotypic and functional heterogeneity points to their great plasticity and ability to modulate, according to their microenvironment, the acquired immune response and, at the same time, makes their precise classification complex and frequently subject to reviews and improvement. This review will present general aspects of the DC physiology and classification and will address their potential and actual uses in the management of human disease, more specifically cancer, as therapeutic and monitoring tools. New combination treatments with the participation of DC will be also discussed.
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Affiliation(s)
- Thiago A Patente
- Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mariana P Pinho
- Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Aline A Oliveira
- Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Gabriela C M Evangelista
- Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Patrícia C Bergami-Santos
- Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - José A M Barbuto
- Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.,Discipline of Molecular Medicine, Department of Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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Shang K, Wei Y, Su Q, Yu B, Tao Y, He Y, Wang Y, Shi G, Duan L. IL-33 Ameliorates the Development of MSU-Induced Inflammation Through Expanding MDSCs-Like Cells. Front Endocrinol (Lausanne) 2019; 10:36. [PMID: 30863362 PMCID: PMC6399133 DOI: 10.3389/fendo.2019.00036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 01/16/2019] [Indexed: 11/15/2022] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 superfamily, has been shown to play a critical role in many diseases through regulating the immune cell responses, including myeloid-derived suppressor cells (MDSCs). Our previous study demonstrated that IL-33 might play a protective role in kidney injury in gout patients by regulating the lipid metabolism. However, the role of IL-33in the development of MSU-induced inflammation remains elusive. In this study, an increased IL-33 expression was observed in gout patients, which was positively correlated with inflammatory marker CRP. To explore the effects and mechanisms of the increased IL-33 expression in the gout patients, the anti-ST2 antibody and exogenous recombinant IL-33 were used in MSU-induced peritonitis animal model that mimics human gout. Compared with control group, mice with exogenous recombinant IL-33 significantly ameliorated the inflammatory cells infiltration, while blockage of IL-33 signaling by anti-ST2 had no effect on the development of MSU-induced peritonitis. Furthermore, the crucial inflammatory cytokine IL-1β was markedly decreased in IL-33-treated mice. Besides that, a large number of anti-inflammatory MDSCs with CD11b+Gr1intF4/80+ phenotype was observed in the IL-33-treated mice, and adoptive transfer of IL-33-induced MDSCs (CD11b+Gr1intF4/80+) markedly inhibited the IL-1β production in MSU-induced peritonitis. In conclusion, our data provide clear evidences that the increased expression of IL-33 in the gout patients might be due to a cause of self-negative regulation, which inhibits the development of MSU-induced inflammation through expanding MDSCs. Thus, IL-33 might serve as a promising therapeutic target for gout.
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Affiliation(s)
- Ke Shang
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Yingying Wei
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Qun Su
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Bing Yu
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Ying Tao
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Yan He
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Youlian Wang
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Guixiu Shi
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Guixiu Shi
| | - Lihua Duan
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital, Nanchang, China
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
- *Correspondence: Lihua Duan
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Prelaj A, Tay R, Ferrara R, Chaput N, Besse B, Califano R. Predictive biomarkers of response for immune checkpoint inhibitors in non-small-cell lung cancer. Eur J Cancer 2018; 106:144-159. [PMID: 30528799 DOI: 10.1016/j.ejca.2018.11.002] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 10/10/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022]
Abstract
Immune checkpoint blockade has been a pivotal development in the management of advanced non-small-cell lung cancer (NSCLC). Although durable antitumour activity and improved survival have been observed in a subset of patients, there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential non-responders. This review will address the use and limitations of tumour programmed death-ligand 1 expression as a predictive biomarker and review emerging biomarker strategies specifically related to NSCLC including genetic alterations (tumour mutation burden, loss and gain activated mutations), tumour-related factors (tumour microenvironment) and factors related to the host immune system. Novel approaches in biomarker detection such as peripheral blood monitoring will also be reviewed.
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Affiliation(s)
- Arsela Prelaj
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Department of Radiological, Pathological and Oncological Science, Sapienza University of Rome, Italy.
| | - Rebecca Tay
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
| | - Roberto Ferrara
- Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, Gustave Roussy, Villejuif, France.
| | - Nathalie Chaput
- Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, Gustave Roussy, Villejuif, France; Faculty of Pharmacy, University Paris-Saclay, Chatenay-Malabry, France.
| | - Benjamin Besse
- Cancer Medicine Department, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France.
| | - Raffaele Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Department of Medical Oncology, Manchester University NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK.
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37
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Kus K, Kij A, Zakrzewska A, Jasztal A, Stojak M, Walczak M, Chlopicki S. Alterations in arginine and energy metabolism, structural and signalling lipids in metastatic breast cancer in mice detected in plasma by targeted metabolomics and lipidomics. Breast Cancer Res 2018; 20:148. [PMID: 30514398 PMCID: PMC6278167 DOI: 10.1186/s13058-018-1075-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 11/06/2018] [Indexed: 01/05/2023] Open
Abstract
Background The early detection of metastasis based on biomarkers in plasma may improve cancer prognosis and guide treatment. The aim of this work was to characterize alterations in metabolites of the arginine pathway, energy metabolism, and structural and signalling lipids in plasma in the early and late stages of murine breast cancer metastasis. Methods Mice were orthotopically inoculated with 4T1 metastatic breast cancer cells, and plasma was analysed along the pulmonary metastasis progression using LC-MS/MS-based targeted metabolomics and lipidomics. Results Based on primary tumour growth and pulmonary metastases, 1–2 weeks after 4T1 cancer cell inoculation was defined as an early metastatic stage, and 3–4 weeks after 4T1 cancer cell inoculation was defined as a late metastatic stage. Early metastasis was featured in plasma by a shift of L-arginine metabolism towards arginase (increased ornithine/arginine ratio) and polyamine synthesis (increased putrescine). Late metastasis was reflected in plasma by further progression of changes in the arginine pathway with an additional increase in asymmetric dimethylarginine plasma concentration, as well as by a profound energy metabolism reprogramming towards glycolysis, an accelerated pentose phosphate pathway and a concomitant decrease in tricarboxylic cycle rate (“Warburg effect”). The late but not the early phase of metastasis was also characterized by a different lipid profile pattern in plasma, including a decrease in total phosphatidylcholines, a decrease in diester-bound phospholipid fraction and an increase in lysophospholipids associated with an increase in total sphingomyelins. Conclusions The early phase of metastasis in murine 4T1 metastatic breast cancer was associated with plasma metabolome changes characteristic of arginase activation and polyamine synthesis. The late metastasis was reflected in plasma not only by the alterations in arginine pathways but also by a shift towards glycolysis and the pentose pathway, remodelling of structural lipids and activation of lipid signalling, all of which coincided with metastasis progression. Electronic supplementary material The online version of this article (10.1186/s13058-018-1075-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kamil Kus
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Agnieszka Kij
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland.,Jagiellonian University Medical College, Chair and Department of Toxicology, Medyczna 9, 30-688, Krakow, Poland
| | - Agnieszka Zakrzewska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Agnieszka Jasztal
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Marta Stojak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Maria Walczak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland.,Jagiellonian University Medical College, Chair and Department of Toxicology, Medyczna 9, 30-688, Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348, Krakow, Poland. .,Jagiellonian University Medical College, Chair of Pharmacology, Grzegorzecka 16, 31-531, Krakow, Poland.
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38
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Budhwar S, Verma P, Verma R, Rai S, Singh K. The Yin and Yang of Myeloid Derived Suppressor Cells. Front Immunol 2018; 9:2776. [PMID: 30555467 PMCID: PMC6280921 DOI: 10.3389/fimmu.2018.02776] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 11/12/2018] [Indexed: 02/06/2023] Open
Abstract
In recent years, most of our knowledge about myeloid derived suppressor cells (MDSCs) has come from cancer studies, which depicts Yin side of MDSCs. In cancer, inherent immunosuppressive action of MDSCs favors tumor progression by inhibiting antitumor immune response. However, recently Yang side of MDSCs has also been worked out and suggests the role in maintenance of homeostasis during non-cancer situations like pregnancy, obesity, diabetes, and autoimmune disorders. Continued work in this area has armored the biological importance of these cells as master regulators of immune system and prompted scientists all over the world to look from a different perspective. Therefore, explicating Yin and Yang arms of MDSCs is obligatory to use it as a double edged sword in a much smarter way. This review is an attempt toward presenting a synergistic coalition of all the facts and controversies that exist in understanding MDSCs, bring them on the same platform and approach their "Yin and Yang" nature in a more comprehensive and coherent manner.
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Affiliation(s)
- Snehil Budhwar
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Priyanka Verma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Rachna Verma
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sangeeta Rai
- Department of Obstetrics and Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Kiran Singh
- Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India
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Elias R, Hartshorn K, Rahma O, Lin N, Snyder-Cappione JE. Aging, immune senescence, and immunotherapy: A comprehensive review. Semin Oncol 2018; 45:187-200. [PMID: 30539714 DOI: 10.1053/j.seminoncol.2018.08.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 07/07/2018] [Accepted: 08/01/2018] [Indexed: 12/22/2022]
Abstract
The advent of immune checkpoint inhibitors (ICIs) has changed the landscape of cancer treatment. Older adults represent the majority of cancer patients; however, direct data evaluating ICIs in this patient population is lacking. Aging is associated with changes in the immune system known as "immunosenescence" that could impact the efficacy and safety profile of ICIs. In this paper, we review aging-associated changes in the immune system as they may relate to cancer and immunotherapy, with mention of the effect of chronic viral infections and frailty. Furthermore, we summarize the current clinical evidence of ICI effectiveness and toxicity among older adults with cancer.
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Affiliation(s)
- Rawad Elias
- Hartford HealthCare Cancer Institute, Hartford Hospital, Hartford, CT, USA.
| | - Kevan Hartshorn
- Section of Hematology Oncology, Boston University School of Medicine, Boston, MA, USA
| | - Osama Rahma
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nina Lin
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, MA, USA
| | - Jennifer E Snyder-Cappione
- Department of Microbiology, Boston University School of Medicine, Boston, MA, USA; Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, USA
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Wallace K, Lewin DN, Sun S, Spiceland CM, Rockey DC, Alekseyenko AV, Wu JD, Baron JA, Alberg AJ, Hill EG. Tumor-Infiltrating Lymphocytes and Colorectal Cancer Survival in African American and Caucasian Patients. Cancer Epidemiol Biomarkers Prev 2018; 27:755-761. [PMID: 29769214 PMCID: PMC6449046 DOI: 10.1158/1055-9965.epi-17-0870] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 12/08/2017] [Accepted: 05/08/2018] [Indexed: 12/11/2022] Open
Abstract
Background: Compared with Caucasian Americans (CAs), African Americans (AAs) with colorectal cancer have poorer survival, especially younger-age patients. A robust lymphocytic reaction within colorectal cancers is strongly associated with better survival, but whether immune response impacts the disparity in colorectal cancer survival is unknown.Methods: The study population was comprised of 211 histologically confirmed colorectal cancers at the Medical University of South Carolina (Charleston, SC; 159 CAs and 52 AAs) diagnosed between Jan 01, 2000, and June 30, 2013. We constructed a lymphocyte score based on blinded pathologic assessment of the four different types of lymphocytic reactions. Cox proportional hazards regression was used to evaluate the association between the lymphocyte score and risk of death by race.Results: Colorectal cancers in AAs (vs. CAs) had a stronger lymphocytic reaction at diagnosis. A high lymphocyte score (vs. the lowest) was associated with better survival in AAs [HR 0.19; 95% confidence interval (CI), 0.04-0.99] and CAs (HR 0.47; 95% CI, 0.15-1.45). AAs with no lymphocytic reaction (vs. other categories) had poor survival HR 4.48 (1.58-12.7) whereas no difference was observed in CAs. The risk of death in AAs (vs. CA) was more pronounced in younger patients (HR 2.92; 95% CI, 1.18-7.22) compared with older (HR 1.20; 95% CI, 0.54-2.67), especially those with lymphocytic poor colorectal cancers.Conclusions: The lymphocytic reaction in tumor impacted the racial disparity in survival.Impact: Our results confirm the importance of the lymphocytic score on survival and highlight the need to fully characterize the immune environment of colorectal cancers by race. Cancer Epidemiol Biomarkers Prev; 27(7); 755-61. ©2018 AACR.
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Affiliation(s)
- Kristin Wallace
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - David N Lewin
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Shaoli Sun
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Clayton M Spiceland
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Don C Rockey
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Alexander V Alekseyenko
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Jennifer D Wu
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - John A Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Anthony J Alberg
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Elizabeth G Hill
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
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Thyagarajan A, Sahu RP. Potential Contributions of Antioxidants to Cancer Therapy: Immunomodulation and Radiosensitization. Integr Cancer Ther 2018; 17:210-216. [PMID: 28627256 PMCID: PMC6041931 DOI: 10.1177/1534735416681639] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 11/01/2016] [Accepted: 11/02/2016] [Indexed: 12/18/2022] Open
Abstract
Antioxidants play important roles in the maintenance of cellular integrity and thus are critical in maintaining the homeostasis of the host immune system. A balance between the levels of pro-oxidants and antioxidants defines the cellular fate of genomic integrity via maintaining the redox status of the cells. An aberration in this balance modulates host immunity that affects normal cellular signaling pathways resulting in uncontrolled proliferation of cells leading to neocarcinogenesis. For decades, there have been scientific debates on the use of antioxidants for the treatment of human cancers. This review is focused on current updates on the implications of antioxidant use as adjuncts in cancer therapy with an emphasis on immunomodulation and radiosensitization.
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Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol 2018; 59:391-412. [PMID: 29730580 PMCID: PMC7106078 DOI: 10.1016/j.intimp.2018.03.002] [Citation(s) in RCA: 451] [Impact Index Per Article: 64.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 02/07/2023]
Abstract
The immune system is a very diverse system of the host that evolved during evolution to cope with various pathogens present in the vicinity of environmental surroundings inhabited by multicellular organisms ranging from achordates to chordates (including humans). For example, cells of immune system express various pattern recognition receptors (PRRs) that detect danger via recognizing specific pathogen-associated molecular patterns (PAMPs) and mount a specific immune response. Toll-like receptors (TLRs) are one of these PRRs expressed by various immune cells. However, they were first discovered in the Drosophila melanogaster (common fruit fly) as genes/proteins important in embryonic development and dorso-ventral body patterning/polarity. Till date, 13 different types of TLRs (TLR1-TLR13) have been discovered and described in mammals since the first discovery of TLR4 in humans in late 1997. This discovery of TLR4 in humans revolutionized the field of innate immunity and thus the immunology and host-pathogen interaction. Since then TLRs are found to be expressed on various immune cells and have been targeted for therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is reviewed.
TLRs are first described PRRs that revolutionized the biology of host-pathogen interaction and immune response The discovery of different TLRs in humans proved milestone in the field of innate immunity and inflammation The pattern of expression of all the TLRs expressed by human immune cells An association of various TLR SNPs with different inflammatory diseases Currently available drugs or vaccines based on TLRs and their future in drug targeting along with the role in reproduction, and regeneration
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Mohapatra SS, Batra SK, Bharadwaj S, Bouvet M, Cosman B, Goel A, Jogunoori W, Kelley MJ, Mishra L, Mishra B, Mohapatra S, Patel B, Pisegna JR, Raufman JP, Rao S, Roy H, Scheuner M, Singh S, Vidyarthi G, White J. Precision Medicine for CRC Patients in the Veteran Population: State-of-the-Art, Challenges and Research Directions. Dig Dis Sci 2018; 63:1123-1138. [PMID: 29572615 PMCID: PMC5895694 DOI: 10.1007/s10620-018-5000-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 02/23/2018] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA's research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC.
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Affiliation(s)
- Shyam S. Mohapatra
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- James A. Haley Veterans Hospital, Tampa, FL USA
- Division of Translational Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL USA
- College of Pharmacy Graduate Programs, University of South Florida, Tampa, FL USA
| | - Surinder K. Batra
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- Department of Biochemistry and Molecular Biology, Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE USA
| | - Srinivas Bharadwaj
- Division of Translational Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Michael Bouvet
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- VA San Diego Healthcare System, San Diego, CA USA
- Department of Surgery, University of California San Diego Moores Cancer Center, San Diego, CA USA
| | - Bard Cosman
- VA San Diego Healthcare System, San Diego, CA USA
- Department of Surgery, University of California San Diego Moores Cancer Center, San Diego, CA USA
| | - Ajay Goel
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Dallas, TX, USA
- Charles A. Sammons Cancer Center, Baylor University, Dallas, TX USA
| | - Wilma Jogunoori
- Washington DC VA Medical Center, Washington, DC USA
- Department of Surgery, Center for Translational Medicine, George Washington University, Washington, DC USA
| | - Michael J. Kelley
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- National Oncology Program Office, Specialty Care Services, Department of Veterans Affairs, Durham VA Medical Center, Durham, NC USA
- Department of Medicine, Duke University Medical Center, Durham, NC USA
| | - Lopa Mishra
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- Washington DC VA Medical Center, Washington, DC USA
- Department of Surgery, Center for Translational Medicine, George Washington University, Washington, DC USA
| | - Bibhuti Mishra
- Washington DC VA Medical Center, Washington, DC USA
- Department of Surgery, Center for Translational Medicine, George Washington University, Washington, DC USA
| | - Subhra Mohapatra
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- James A. Haley Veterans Hospital, Tampa, FL USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Bhaumik Patel
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- Hunter Holmes McGuire VA Medical Center and Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA USA
| | - Joseph R. Pisegna
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- Division of Gastroenterology and Human Genetics, VA Greater Los Angeles Healthcare System, Los Angeles, CA USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
| | - Jean-Pierre Raufman
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- VA Maryland Health Care System, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD USA
| | - Shuyun Rao
- Washington DC VA Medical Center, Washington, DC USA
- Department of Surgery, Center for Translational Medicine, George Washington University, Washington, DC USA
| | - Hemant Roy
- Department of Medicine, Boston University School of Medicine, Boston, MA USA
| | - Maren Scheuner
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- Division of Gastroenterology and Human Genetics, VA Greater Los Angeles Healthcare System, Los Angeles, CA USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
| | - Satish Singh
- Department of Veterans Affairs Colorectal Cancer Cell-genomics Consortium [VA4C], Tampa, FL USA
- VA Boston Healthcare System and Department of Medicine, Boston University School of Medicine, Boston, MA USA
| | - Gitanjali Vidyarthi
- James A. Haley Veterans Hospital, Tampa, FL USA
- Division of Translational Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Jon White
- Washington DC VA Medical Center, Washington, DC USA
- Department of Surgery, Center for Translational Medicine, George Washington University, Washington, DC USA
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44
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Arnold KM, Flynn NJ, Raben A, Romak L, Yu Y, Dicker AP, Mourtada F, Sims-Mourtada J. The Impact of Radiation on the Tumor Microenvironment: Effect of Dose and Fractionation Schedules. CANCER GROWTH AND METASTASIS 2018; 11:1179064418761639. [PMID: 29551910 PMCID: PMC5846913 DOI: 10.1177/1179064418761639] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 10/23/2017] [Indexed: 02/06/2023]
Abstract
In addition to inducing lethal DNA damage in tumor and stromal cells, radiation can alter the interactions of tumor cells with their microenvironment. Recent technological advances in planning and delivery of external beam radiotherapy have allowed delivery of larger doses per fraction (hypofractionation) while minimizing dose to normal tissues with higher precision. The effects of radiation on the tumor microenvironment vary with dose and fractionation schedule. In this review, we summarize the effects of conventional and hypofractionated radiation regimens on the immune system and tumor stroma. We discuss how these interactions may provide therapeutic benefit in combination with targeted therapies. Understanding the differential effects of radiation dose and fractionation can have implications for choice of combination therapies.
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Affiliation(s)
- Kimberly M Arnold
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE, USA.,Department of Medical Laboratory Sciences, University of Delaware, Newark, DE, USA
| | - Nicole J Flynn
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE, USA.,Department of Biological Sciences, University of Delaware, Newark, DE, USA
| | - Adam Raben
- Department of Radiation Oncology, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE, USA
| | - Lindsay Romak
- Department of Radiation Oncology, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE, USA
| | - Yan Yu
- Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Adam P Dicker
- Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Firas Mourtada
- Department of Radiation Oncology, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE, USA.,Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jennifer Sims-Mourtada
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE, USA.,Department of Medical Laboratory Sciences, University of Delaware, Newark, DE, USA.,Department of Biological Sciences, University of Delaware, Newark, DE, USA
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45
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Escande A, Haie-Meder C, Maroun P, Gouy S, Mazeron R, Leroy T, Bentivegna E, Morice P, Deutsch E, Chargari C. Neutrophilia in locally advanced cervical cancer: A novel biomarker for image-guided adaptive brachytherapy? Oncotarget 2018; 7:74886-74894. [PMID: 27713124 PMCID: PMC5342709 DOI: 10.18632/oncotarget.12440] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/19/2016] [Indexed: 12/24/2022] Open
Abstract
Objective To study the prognostic value of leucocyte disorders in a prospective cohort of cervical cancer patients receiving definitive chemoradiation plus image—guided adaptive brachytherapy (IGABT). Results 113 patients were identified. All patients received a pelvic irradiation concomitant with chemotherapy, extended to the para-aortic area in 13 patients with IVB disease. Neutrophilia and leukocytosis were significant univariate prognostic factors for poorer local failure-free survival (p = 0.000 and p = 0.002, respectively), associated with tumor size, high-risk clinical target volume (HR-CTV) and anemia. No effect was shown for distant metastases but leukocytosis and neutrophila were both poor prognostic factors for in-field relapses (p = 0.003 and p < 0.001). In multivariate analysis, HR-CTV volume (p = 0.026) and neutrophils count > 7,500/μl (p = 0.018) were independent factors for poorer survival without local failure, with hazard ratio (HR) of 3.1. Materials and methods We examined patients treated in our Institution between April 2009 and July 2015 by concurrent chemoradiation (45 Gy in 25 fractions +/− lymph node boosts) followed by a magnetic resonance imaging (MRI)-guided adaptive pulse-dose rate brachytherapy (15 Gy to the intermediate-risk clinical target volume). The prognostic value of pretreatment leucocyte disorders was examined. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophils count exceeding 10,000 and 7,500/μl, respectively. Conclusions Neutrophilia is a significant prognostic factor for local relapse in locally advanced cervical cancer treated with MRI-based IGABT. This biomarker could help identifying patients with higher risk of local relapse and requiring dose escalation.
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Affiliation(s)
- Alexandre Escande
- Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Christine Haie-Meder
- Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Pierre Maroun
- Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France.,Faculté de Médecine PARIS Sud, Université Paris Sud, Université Paris Saclay, France
| | - Sébastien Gouy
- Department of Surgery, Gustave Roussy, Villejuif, France
| | - Renaud Mazeron
- Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Thomas Leroy
- Radiotherapy Department, Oscar Lambret Comprehensive Cancer Center, Lille, France
| | | | - Philippe Morice
- Faculté de Médecine PARIS Sud, Université Paris Sud, Université Paris Saclay, France.,Department of Surgery, Gustave Roussy, Villejuif, France.,INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France
| | - Eric Deutsch
- Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France.,Faculté de Médecine PARIS Sud, Université Paris Sud, Université Paris Saclay, France.,INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France
| | - Cyrus Chargari
- Radiotherapy Department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France.,Faculté de Médecine PARIS Sud, Université Paris Sud, Université Paris Saclay, France.,INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France.,French Military Health Services Academy, Ecole du Val-de-Grâce, Paris, France.,Institut de Recherche Biomédicale des Armées, Bretigny-sur-Orge, France
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Janssen N, Speigl L, Pawelec G, Niessner H, Shipp C. Inhibiting HSP90 prevents the induction of myeloid-derived suppressor cells by melanoma cells. Cell Immunol 2018; 327:68-76. [PMID: 29478948 DOI: 10.1016/j.cellimm.2018.02.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/18/2018] [Indexed: 12/19/2022]
Abstract
Metastatic melanoma is the most dangerous form of skin cancer, with an ever-increasing incidence worldwide. Despite encouraging results with immunotherapeutic approaches, long-term survival is still poor. This is likely partly due to tumour-induced immune suppression mediated by myeloid-derived suppressor cells (MDSCs), which were shown to be associated with response to therapy and survival. Thus, identifying pathways responsible for MDSC differentiation may provide new therapeutic targets and improve efficacy of existing immunotherapies. Therefore, we've analysed mechanisms by which tumour cells contribute to the induction of MDSCs. Established melanoma cell lines were pre-treated with inhibitors of different pathways and tested for their capacity to alleviate T cell suppression via MDSC differentiation in vitro. Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions. This initial study suggests a novel mechanism in tumour cells responsible for the induction of MDSC in melanoma.
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Affiliation(s)
- Nicole Janssen
- Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany.
| | - Lisa Speigl
- Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
| | - Graham Pawelec
- Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany; Health Sciences North Research Institute, Sudbury, ON, Canada; School of Science and Technology, College of Arts and Science, Nottingham Trent University, Nottingham, United Kingdom; Department of Haematological Medicine, King's College London, The Rayne Institute, London, United Kingdom
| | - Heike Niessner
- Section of Dermatooncology, University Hospital Tübingen, Tübingen, Germany
| | - Christopher Shipp
- Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
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47
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Pereira MB, Barros LRC, Bracco PA, Vigo A, Boroni M, Bonamino MH, Lenz G. Transcriptional characterization of immunological infiltrates and their relation with glioblastoma patients overall survival. Oncoimmunology 2018; 7:e1431083. [PMID: 29872555 DOI: 10.1080/2162402x.2018.1431083] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 01/10/2018] [Accepted: 01/12/2018] [Indexed: 10/18/2022] Open
Abstract
Introduction: Several cell populations from the peripheral immune system interact to create a complex immunologic status during glioblastoma growth and response to therapy. The aim of this study was to integrate the impact of different immune cell populations present in glioblastoma tumor microenvironment on overall survival. Methodology: Gene expression and clinical data were generated by The Cancer Genome Atlas and previously reported meta-signatures representing cells of the immune system were used. The relationship between meta-signatures was evaluated through Pearson's correlation analyses. Survival analyses were performed through Kaplan-Meier plots and Cox regression model. Results and discussion: Meta-signatures corresponding to infiltrating immune cells with immunosuppressive roles, such as macrophages, NK and NK T cells, MDSCs and Tregs, correlated with poorer patient prognosis. Meta-signatures related to CD8+ T cells predicted improved survival only in patients with low immunosuppressive meta-signatures. By clustering the meta-signatures we found that the cluster containing high meta-signatures of macrophages, MDSCs and Tregs demonstrated the worst prognosis. Conclusion: Integrating the information provided by transcriptional signatures of immunological aspects is fundamental in understanding the impact of the immune system on patient survival. We found a predictive impact on survival with positive role for CD8 and negative roles for macrophages, MDSC, Tregs, NK and NK-T in glioblastoma patients. Understanding these regulatory and stimulatory factors of patients' immune system is essential to delineate an effective strategy to increase the anti-tumor immune response and to generate potential clinical benefits.
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Affiliation(s)
- Mariana Brutschin Pereira
- Department of Biophysics and Center of Biotechnology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.,Center of Biotechnology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | | | - Paula A Bracco
- Graduate Program in Epidemiology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Alvaro Vigo
- Departament of Statistics, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.,Graduate Program in Epidemiology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Mariana Boroni
- Bioinformatics and Computacional Biology Lab, National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Martín Hernán Bonamino
- Molecular Carcinogenesis Program, Research Coordination, National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.,FIOCRUZ - Oswaldo Cruz Foundation Institute, Rio de Janeiro, RJ, Brazil
| | - Guido Lenz
- Department of Biophysics and Center of Biotechnology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.,Center of Biotechnology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
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48
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Zeng AQ, Yu Y, Yao YQ, Yang FF, Liao M, Song LJ, Li YL, Yu Y, Li YJ, Deng YL, Yang SP, Zeng CJ, Liu P, Xie YM, Yang JL, Zhang YW, Ye TH, Wei YQ. Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models. Oncotarget 2017; 9:3794-3804. [PMID: 29423083 PMCID: PMC5790500 DOI: 10.18632/oncotarget.23376] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 11/27/2017] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.
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Affiliation(s)
- An-Qi Zeng
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yan Yu
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yu-Qin Yao
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Fang-Fang Yang
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Mengya Liao
- Sichuan Nursing Vocational College, Chengdu 610100, China
| | - Lin-Jiang Song
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Ya-Li Li
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yang Yu
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital Affiliated to the Capital Medical University, Beijing 100038, China
| | - Yu-Jue Li
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yuan-Le Deng
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Shu-Ping Yang
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Chen-Juan Zeng
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.,Sichuan Scientist Biotechnology Co., Ltd, Chengdu 610041, China
| | - Ping Liu
- Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, China
| | - Yong-Mei Xie
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Jin-Liang Yang
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yi-Wen Zhang
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Ting-Hong Ye
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Yu-Quan Wei
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
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Abstract
Human cancers exhibit formidable molecular heterogeneity, to a large extent accounting for the incomplete and transitory efficacy of current anti-cancer therapies. However, neoplastic cells alone do not manifest the disease, but conscript a battery of non-tumor cells to enable and sustain hallmark capabilities of cancer. Escaping immunosurveillance is one of such capabilities. Tumors evolve immunosuppressive microenvironment to subvert anti-tumor immunity. In this review, we will focus on tumor-associated myeloid cells, which constitute an essential part of the immune microenvironment and reciprocally interact with cancer cells to establish malignancy toward metastasis. The diversity and plasticity of these cells constitute another layer of heterogeneity, beyond the heterogeneity of cancer cells themselves. We envision that immune microenvironment co-evolves with the genetic heterogeneity of tumor. Addressing the question of how genetically distinct tumors shape and are shaped by unique immune microenvironment will provide an attractive rationale to develop novel immunotherapeutic modalities. Here, we discuss the complex nature of tumor microenvironment, with an emphasis on the cellular and functional heterogeneity among tumor-associated myeloid cells as well as immune environment heterogeneity in the context of a full spectrum of human breast cancers.
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50
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Immunotherapy comes of age: Immune aging & checkpoint inhibitors. J Geriatr Oncol 2017; 8:229-235. [DOI: 10.1016/j.jgo.2017.02.001] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/08/2017] [Accepted: 02/03/2017] [Indexed: 12/24/2022]
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