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Tian B, Wang Z, Cao M, Wang N, Jia X, Zhang Y, Zhou J, Liu S, Zhang W, Dong X, Li Z, Xue J, Wang J, Fan GH, Li Q. CCR8 antagonist suppresses liver cancer progression via turning tumor-infiltrating Tregs into less immunosuppressive phenotype. J Exp Clin Cancer Res 2025; 44:113. [PMID: 40186298 PMCID: PMC11969927 DOI: 10.1186/s13046-025-03286-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/12/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) are the main immunosuppressive cells in tumor immune microenvironment (TIME). However, systemic Treg depletion is not favored due to the crucial role of Tregs in the maintenance of immune homeostasis and prevention of autoimmunity. Recently, CCR8 has been identified as a key chemokine receptor expressed on tumor-infiltrating Tregs and targeted blockade of CCR8 exerts anticancer effect in several cancer types, but whether this pathway is involved in the progression of hepatocellular carcinoma (HCC) remains unclear. METHODS We determined the involvement of CCR8+ Tregs in HCC using human HCC tissues and TCGA database, and examined the anticancer effect and the underlying molecular mechanisms of the CCR8 antagonist, IPG0521m, which was developed in house, in murine liver cancer model with flow cytometry, bulk and single-cell RNA sequencing and Real-Time PCR. RESULTS Remarkable increase in CCR8+ Tregs was observed in human HCC tissues. Treatment of syngeneic liver cancer model with IPG0521m resulted in dramatic inhibition of tumor growth, associated with increased CD8+ T cells in tumor tissues. Bulk RNA sequencing analysis indicated that IPG0521m treatment resulted in remarkable increase in antitumor immunity. Furthermore, single-cell RNA sequencing analysis demonstrated that IPG0521m treatment resulted in a switch of Tregs from high immunosuppression to low immunosuppression phenotype, associated with elevated CD8+ T and NK cell proliferation and cytotoxicity, and decreased myeloid-derived suppressor cells and tumor-associated macrophages in the tumor tissues. CONCLUSIONS IPG0521m inhibited liver cancer growth via reducing the immunosuppressive function of Tregs, thereby boosting anti-cancer immunity. Our study paves the way for the clinical study of CCR8 antagonist in HCC and other cancers.
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MESH Headings
- Liver Neoplasms/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/genetics
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/metabolism
- Animals
- Mice
- Humans
- Receptors, CCR8/antagonists & inhibitors
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/metabolism
- Disease Progression
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Tumor Microenvironment/drug effects
- Phenotype
- Disease Models, Animal
- Cell Line, Tumor
- Immune Tolerance
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Affiliation(s)
- Binle Tian
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Zhilong Wang
- Department of Oncology, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China
| | - Mei Cao
- Department of Gynecology and Obstetrics, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Na Wang
- Department of Antibody Development, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China
| | - Xuebing Jia
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Yuanyuan Zhang
- Department of Oncology, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China
| | - Jingyi Zhou
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Sijia Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
| | - Wen Zhang
- Department of Oncology, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China
| | - Xiao Dong
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Zheng Li
- Department of Autoimmune Disease, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
| | - JianFei Wang
- Excecutive Office, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China.
- Shanghai Laboratory Animal Research Center, Shanghai, 201203, China.
| | - Guo-Huang Fan
- Excecutive Office, Immunophage Biotech Co., Ltd., 10 Lv Zhouhuang Road, Shanghai, 201114, China.
| | - Qi Li
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
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Zhang Y, Yan Z, Jiao Y, Feng Y, Zhang S, Yang A. Innate Immunity in Helicobacter pylori Infection and Gastric Oncogenesis. Helicobacter 2025; 30:e70015. [PMID: 40097330 PMCID: PMC11913635 DOI: 10.1111/hel.70015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 01/25/2025] [Accepted: 01/25/2025] [Indexed: 03/19/2025]
Abstract
Helicobacter pylori is an extremely common cause of gastritis that can lead to gastric adenocarcinoma over time. Approximately half of the world's population is infected with H. pylori, making gastric cancer the fourth leading cause of cancer-related deaths worldwide. Innate immunity significantly contributes to systemic and local immune responses, maintains homeostasis, and serves as the vital link to adaptive immunity, and in doing so, mediates H. pylori infection outcomes and consequent cancer risk and development. The gastric innate immune system, composed of gastric epithelial and myeloid cells, is uniquely challenged by its need to interact simultaneously and precisely with commensal microbiota, exogenous pathogens, ingested substances, and endogenous exfoliated cells. Additionally, innate immunity can be detrimental by promoting chronic infection and fibrosis, creating an environment conducive to tumor development. This review summarizes and discusses the complex role of innate immunity in H. pylori infection and subsequent gastric oncogenesis, and in doing so, provides insights into how these pathways can be exploited to improve prevention and treatment.
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Affiliation(s)
- Yuheng Zhang
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Eight‐Year Medical Doctor Program, Peking Union Medical CollegeChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Zhiyu Yan
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Department of Medicine, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yuhao Jiao
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
- Department of Medicine, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yunlu Feng
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Shengyu Zhang
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Aiming Yang
- Department of Gastroenterology, Peking Union Medical College HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
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Kapor S, Radojković M, Santibanez JF. Myeloid-derived suppressor cells: Implication in myeloid malignancies and immunotherapy. Acta Histochem 2024; 126:152183. [PMID: 39029317 DOI: 10.1016/j.acthis.2024.152183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024]
Abstract
Myeloid malignancies stem from a modified hematopoietic stem cell and predominantly include acute myeloid leukemia, myelodysplastic neoplasms, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory properties by governing the innate and adaptive immune systems, creating a permissive and supportive environment for neoplasm growth. This review examines the key characteristics of MDSCs in myeloid malignancies, highlighting that an increased MDSC count corresponds to heightened immunosuppressive capabilities, fostering an immune-tolerant neoplasm microenvironment. Also, this review analyzes and describes the potential of combined cancer therapies, focusing on targeting MDSC generation, expansion, and their inherent immunosuppressive activities to enhance the efficacy of current cancer immunotherapies. A comprehensive understanding of the implications of myeloid malignancies may enhance the exploration of immunotherapeutic strategies for their potential application.
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Affiliation(s)
- Suncica Kapor
- Department of Hematology, Clinical, and Hospital Center "Dr. Dragiša Mišović-Dedinje,", Heroja Milana Tepića 1, Belgrade 11020, Serbia
| | - Milica Radojković
- Department of Hematology, Clinical, and Hospital Center "Dr. Dragiša Mišović-Dedinje,", Heroja Milana Tepića 1, Belgrade 11020, Serbia; Faculty of Medicine, University of Belgrade, Dr. Subotića Starijeg 8, Belgrade 11000, Serbia
| | - Juan F Santibanez
- Molecular Oncology group, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, Dr. Subotica 4, POB 102, Belgrade 11129, Serbia; Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O Higgins, General Gana 1780, Santiago 8370854, Chile.
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Kolecka-Bednarczyk A, Frydrychowicz M, Budny B, Ruciński M, Dompe C, Gabryel P, Płachno BJ, Ruchała M, Ziemnicka K, Zieliński P, Budna-Tukan J. Specific Deletions of Chromosomes 3p, 5q, 13q, and 21q among Patients with G2 Grade of Non-Small Cell Lung Cancer. Int J Mol Sci 2024; 25:8642. [PMID: 39201328 PMCID: PMC11354976 DOI: 10.3390/ijms25168642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 09/02/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) leads as a primary cause of cancer-related premature mortality in Western populations. This study leverages cutting-edge gene-expression-profiling technologies to perform an in-depth molecular characterization of NSCLC specimens, with the objective of uncovering tumor-specific genomic alterations. By employing DNA microarray analysis, our research aims to refine the classification of NSCLC for early detection, guide molecular-targeted treatment approaches, enhance prognostication, and broaden the scientific understanding of the disease's biology. We identified widespread genomic abnormalities in our samples, including the recurrent loss of chromosomal regions 3p, 5q, 13q, and 21q and the gain of 12p. Furthermore, utilizing Metascape for bioinformatic analysis revealed critical biological pathways disrupted in NSCLC, offering promising leads for novel therapeutic interventions.
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Affiliation(s)
- Agata Kolecka-Bednarczyk
- Department of Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (M.F.); (C.D.)
| | - Magdalena Frydrychowicz
- Department of Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (M.F.); (C.D.)
| | - Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (B.B.); (M.R.); (K.Z.)
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.R.); (J.B.-T.)
| | - Claudia Dompe
- Department of Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (M.F.); (C.D.)
- Doctoral School, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Piotr Gabryel
- Department of Thoracic Surgery, Poznan University of Medical Sciences, 60-569 Poznan, Poland; (P.G.); (P.Z.)
| | - Bartosz J. Płachno
- Department of Plant Cytology and Embryology, Institute of Botany, Faculty of Biology, Jagiellonian University in Kraków, 30-387 Cracow, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (B.B.); (M.R.); (K.Z.)
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (B.B.); (M.R.); (K.Z.)
| | - Paweł Zieliński
- Department of Thoracic Surgery, Poznan University of Medical Sciences, 60-569 Poznan, Poland; (P.G.); (P.Z.)
| | - Joanna Budna-Tukan
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.R.); (J.B.-T.)
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Gora, 65-046 Zielona Gora, Poland
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Ouyang P, Wang L, Wu J, Tian Y, Chen C, Li D, Yao Z, Chen R, Xiang G, Gong J, Bao Z. Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors. Front Immunol 2024; 15:1344272. [PMID: 38545114 PMCID: PMC10965539 DOI: 10.3389/fimmu.2024.1344272] [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: 11/25/2023] [Accepted: 02/26/2024] [Indexed: 04/12/2024] Open
Abstract
Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most 'cold' tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from 'cold' to 'hot' tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells' ability to recognize and eliminate tumor cells. In 'cold' tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy's efficacy. Concurrently, strategies to convert 'cold' tumors into 'hot' ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting 'cold' tumors.
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Affiliation(s)
- Peng Ouyang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Lijuan Wang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Jianlong Wu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Yao Tian
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Caiyun Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Dengsheng Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Zengxi Yao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Ruichang Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Jin Gong
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Zhen Bao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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6
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Wu L, Liu X, Lei J, Zhang N, Zhao H, Zhang J, Deng H, Li Y. Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells. J Immunother Cancer 2023; 11:e008081. [PMID: 38056898 PMCID: PMC10711877 DOI: 10.1136/jitc-2023-008081] [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] [Accepted: 11/20/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer. METHODS The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs. RESULTS Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy. CONCLUSION These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.
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Affiliation(s)
- Lei Wu
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
| | - Xudong Liu
- School of Medicine, Chongqing University, Chongqing, China
| | - Juan Lei
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Nan Zhang
- School of Medicine, Chongqing University, Chongqing, China
| | - Huakan Zhao
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Jiangang Zhang
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Huan Deng
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
- School of Medicine, Chongqing University, Chongqing, China
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Ottaiano A, Ianniello M, Santorsola M, Ruggiero R, Sirica R, Sabbatino F, Perri F, Cascella M, Di Marzo M, Berretta M, Caraglia M, Nasti G, Savarese G. From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies. BIOLOGY 2023; 12:1183. [PMID: 37759584 PMCID: PMC10525472 DOI: 10.3390/biology12091183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023]
Abstract
Cancer manifests as a multifaceted disease, characterized by aberrant cellular proliferation, survival, migration, and invasion. Tumors exhibit variances across diverse dimensions, encompassing genetic, epigenetic, and transcriptional realms. This heterogeneity poses significant challenges in prognosis and treatment, affording tumors advantages through an increased propensity to accumulate mutations linked to immune system evasion and drug resistance. In this review, we offer insights into tumor heterogeneity as a crucial characteristic of cancer, exploring the difficulties associated with measuring and quantifying such heterogeneity from clinical and biological perspectives. By emphasizing the critical nature of understanding tumor heterogeneity, this work contributes to raising awareness about the importance of developing effective cancer therapies that target this distinct and elusive trait of cancer.
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Affiliation(s)
- Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Monica Ianniello
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Raffaella Ruggiero
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
| | - Roberto Sirica
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
| | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy;
| | - Francesco Perri
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Marco Cascella
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Massimiliano Di Marzo
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy;
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, Italy;
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy; (M.S.); (F.P.); (M.C.); (M.D.M.); (G.N.)
| | - Giovanni Savarese
- AMES, Centro Polidiagnostico Strumentale srl, Via Padre Carmine Fico 24, 80013 Casalnuovo Di Napoli, Italy; (M.I.); (R.R.); (R.S.); (G.S.)
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Shokati E, Safari E. The immunomodulatory role of exosomal microRNA networks in the crosstalk between tumor-associated myeloid-derived suppressor cells and tumor cells. Int Immunopharmacol 2023; 120:110267. [PMID: 37276829 DOI: 10.1016/j.intimp.2023.110267] [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] [Received: 11/22/2022] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/07/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are considered a heterogeneous group of immature myeloid cells engaging in aggressive tumor progression and metastasis in the tumor microenvironment (TME) of patients diagnosed with cancer, through downregulation of anti-tumor immune responses. Exosomes are small vesicles carrying specific cargos, including proteins, lipids, and MicroRNA (miRNAs). Such exosomal miRNAs delivered by MDSCs and tumor cells are short noncoding RNAs mediating some of the immunosuppressive characteristics of MDSCs in the TME. However, when it comes to cancer diseases, how these miRNAs interact with MDSCs and encourage MDSCs differentiation and function need further investigations. In this review, we discuss MDSC-derived exosomal miRNAs and those derived from tumor cells (TDE) could modulate anti-tumor immunity and regulate the interaction between tumor cells and MDSCs in the TME. Afterward, we focus on dividing miRNAs, as an important substance interacting with MDSCs and tumor cells in the TME, into those have an immunosuppressive or stimulating effect not only on MDSCs expansion, differentiation, and suppressive function but also on tumor evasion.
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Affiliation(s)
- Elham Shokati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
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Jiao Y, Yan Z, Yang A. The Roles of Innate Lymphoid Cells in the Gastric Mucosal Immunology and Oncogenesis of Gastric Cancer. Int J Mol Sci 2023; 24:ijms24076652. [PMID: 37047625 PMCID: PMC10095467 DOI: 10.3390/ijms24076652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/25/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023] Open
Abstract
Innate lymphoid cells (ILCs) are a group of innate immune cells that have garnered considerable attention due to their critical roles in regulating immunity and tissue homeostasis. They are particularly abundant in the gastrointestinal tract, where they have been shown to interact with commensal bacteria, pathogens, and other components of the local microenvironment to influence host immune responses to infection and oncogenesis. Their tissue-residency properties enable gastric ILCs a localized and rapid response to alert and stress, which indicates their key potential in regulating immunosurveillance. In this review, we discuss the current understanding of the role of ILCs in the gastric mucosa, with a focus on their interactions with the gastric microbiota and Helicobacter pylori and their contributions to tissue homeostasis and inflammation. We also highlight recent findings on the involvement of ILCs in the pathogenesis of gastric cancer and the implications of targeting ILCs as a therapeutic approach. Overall, this review provides an overview of the diverse functions of ILCs in gastric mucosa and highlights their potential as targets for future therapies for gastric cancer.
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Affiliation(s)
- Yuhao Jiao
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Zhiyu Yan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- 4 + 4 M.D. Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Aiming Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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Zhang C, Fei Y, Wang H, Hu S, Liu C, Hu R, Du Q. CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy? Front Pharmacol 2023; 14:1113378. [PMID: 37007004 PMCID: PMC10064291 DOI: 10.3389/fphar.2023.1113378] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/23/2023] [Indexed: 03/15/2023] Open
Abstract
Cancer immunotherapy has opened a new landscape in cancer treatment, however, the poor specificity and resistance of most targeted therapeutics have limited their therapeutic efficacy. In recent years, the role of CAFs in immune regulation has been increasingly noted as more evidence has been uncovered regarding the link between cancer-associated fibroblasts (CAFs) and the evolutionary process of tumor progression. CAFs interact with immune cells to shape the tumor immune microenvironment (TIME) that favors malignant tumor progression, a crosstalk process that leads to the failure of cancer immunotherapies. In this review, we outline recent advances in the immunosuppressive function of CAFs, highlight the mechanisms of CAFs-immune cell interactions, and discuss current CAF-targeted therapeutic strategies for future study.
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Affiliation(s)
- Chunxue Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yuxiang Fei
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hui Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Sheng Hu
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Chao Liu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Qianming Du, ; Rong Hu, ; Chao Liu,
| | - Rong Hu
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu Nanjing, China
- *Correspondence: Qianming Du, ; Rong Hu, ; Chao Liu,
| | - Qianming Du
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Qianming Du, ; Rong Hu, ; Chao Liu,
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11
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Xu D, Li C, Xu Y, Huang M, Cui D, Xie J. Myeloid-derived suppressor cell: A crucial player in autoimmune diseases. Front Immunol 2022; 13:1021612. [PMID: 36569895 PMCID: PMC9780445 DOI: 10.3389/fimmu.2022.1021612] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are identified as a highly heterogeneous group of immature cells derived from bone marrow and play critical immunosuppressive functions in autoimmune diseases. Accumulating evidence indicates that the pathophysiology of autoimmune diseases was closely related to genetic mutations and epigenetic modifications, with the latter more common. Epigenetic modifications, which involve DNA methylation, covalent histone modification, and non-coding RNA-mediated regulation, refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. Recently, numerous reports have shown that epigenetic modifications in MDSCs play important roles in the differentiation and development of MDSCs and their suppressive functions. The molecular mechanisms of differentiation and development of MDSCs and their regulatory roles in the initiation and progression of autoimmune diseases have been extensively studied, but the exact function of MDSCs remains controversial. Therefore, the biological and epigenetic regulation of MDSCs in autoimmune diseases still needs to be further characterized. This review provides a detailed summary of the current research on the regulatory roles of DNA methylation, histone modifications, and non-coding RNAs in the development and immunosuppressive activity of MDSCs, and further summarizes the distinct role of MDSCs in the pathogenesis of autoimmune diseases, in order to provide help for the diagnosis and treatment of diseases from the perspective of epigenetic regulation of MDSCs.
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Affiliation(s)
- Dandan Xu
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China
| | - Cheng Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yushan Xu
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China
| | - Mingyue Huang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China,*Correspondence: Dawei Cui, ; Jue Xie,
| | - Jue Xie
- Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Hangzhou, Zhejiang University, China,*Correspondence: Dawei Cui, ; Jue Xie,
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12
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Hasselbalch H, Skov V, Kjær L, Larsen MK, Knudsen TA, Lucijanić M, Kusec R. Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives. Cancers (Basel) 2022; 14:5495. [PMID: 36428587 PMCID: PMC9688061 DOI: 10.3390/cancers14225495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 11/12/2022] Open
Abstract
About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies-e.g., immune-checkpoint inhibitors-are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)-i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis-and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-β (rIFN-β)-has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-β as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-β in patients with MPNs.
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Affiliation(s)
- Hans Hasselbalch
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | | | - Trine A. Knudsen
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Marko Lucijanić
- Department of Hematology, University Hospital Dubrava, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Rajko Kusec
- Department of Hematology, University Hospital Dubrava, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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13
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Liu Z, Xiang Y, Zheng Y, Kang X. Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology. Front Immunol 2022; 13:1027124. [PMID: 36341334 PMCID: PMC9630919 DOI: 10.3389/fimmu.2022.1027124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/10/2022] [Indexed: 09/07/2024] Open
Abstract
Immune checkpoint blockade (ICB) has gained unparalleled success in the treatment of colorectal cancer (CRC). However, undesired side effects, unsatisfactory response rates, tumor metastasis, and drug resistance still hinder the further application of ICB therapy against CRC. Advancing ICB with nanotechnology can be game-changing. With the development of immuno-oncology and nanomaterials, various nanoplatforms have been fabricated to enhance the efficacy of ICB in CRC treatment. Herein, this review systematically summarizes these recent nano-strategies according to their mechanisms. Despite their diverse and complex designs, these nanoplatforms have four main mechanisms in enhancing ICB: 1) targeting immune checkpoint inhibitors (ICIs) to tumor foci, 2) increasing tumor immunogenicity, 3) remodeling tumor microenvironment, and 4) pre-sensitizing immune systems. Importantly, advantages of nanotechnology in CRC, such as innovating the mode-of-actions of ICB, modulating intestinal microbiome, and integrating the whole process of antigen presentation, are highlighted in this review. In general, this review describes the latest applications of nanotechnology for CRC immunotherapy, and may shed light on the future design of ICB platforms.
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Affiliation(s)
- Zefan Liu
- Department of General Surgery, First People's Hospital of Shuangliu District, Chengdu, China
| | - Yucheng Xiang
- Department of General Surgery, First People's Hospital of Shuangliu District, Chengdu, China
| | - Yaxian Zheng
- Department of Pharmacy, Third People’s Hospital of Chengdu, Chengdu, China
| | - Xin Kang
- Department of General Surgery, First People's Hospital of Shuangliu District, Chengdu, China
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14
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Yu L, Sun M, Zhang Q, Zhou Q, Wang Y. Harnessing the immune system by targeting immune checkpoints: Providing new hope for Oncotherapy. Front Immunol 2022; 13:982026. [PMID: 36159789 PMCID: PMC9498063 DOI: 10.3389/fimmu.2022.982026] [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: 06/30/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
With the goal of harnessing the host's immune system to provide long-lasting remission and cures for various cancers, the advent of immunotherapy revolutionized the cancer therapy field. Among the current immunotherapeutic strategies, immune checkpoint blockades have greatly improved the overall survival rates in certain patient populations. Of note, CTLA4 and PD-1/PD-L1 are two major non-redundant immune checkpoints implicated in promoting cancer immune evasion, and ultimately lead to relapse. Antibodies or inhibitors targeting these two c+heckpoints have achieved some encouraging clinical outcomes. Further, beyond the canonical immune checkpoints, more inhibitory checkpoints have been identified. Herein, we will summarize recent progress in immune checkpoint blockade therapies, with a specific focus on key pre-clinical and clinical results of new immune checkpoint therapies for cancer. Given the crucial roles of immune checkpoint blockade in oncotherapy, drugs targeting checkpoint molecules expressed by both cancer and immune cells are in clinical trials, which will be comprehensively summarized in this review. Taken together, investigating combinatorial therapies targeting immune checkpoints expressed by cancer cells and immune cells will greatly improve immunotherapies that enhance host elimination of tumors.
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Affiliation(s)
- Lu Yu
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Minghan Sun
- Central of Reproductive Medicine, Department of Obstetrics and Gynecology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Institute of Organ Transplantation, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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15
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Aria H, Rezaei M, Nazem S, Daraei A, Nikfar G, Mansoori B, Bahmanyar M, Tavassoli A, Vakil MK, Mansoori Y. Purinergic receptors are a key bottleneck in tumor metabolic reprogramming: The prime suspect in cancer therapeutic resistance. Front Immunol 2022; 13:947885. [PMID: 36072596 PMCID: PMC9444135 DOI: 10.3389/fimmu.2022.947885] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells' glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.
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Affiliation(s)
- Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Nazem
- Department of Laboratory Medicine, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolreza Daraei
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ghasem Nikfar
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Behnam Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Maryam Bahmanyar
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Alireza Tavassoli
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Mohammad Kazem Vakil
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
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16
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Guo J, Shen Y, Hu S, Rui T, Liu J, Yuan Y. Neobavaisoflavone inhibits antitumor immunosuppression via myeloid-derived suppressor cells. Int Immunopharmacol 2022; 111:109103. [PMID: 35944461 DOI: 10.1016/j.intimp.2022.109103] [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: 05/20/2022] [Revised: 07/16/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022]
Abstract
Neobavaisoflavone (Neo), as a traditional Chinese medicine, is the active ingredient in the herb Psoralea corylifolial and has antitumor activity. Myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of haematopoietic cells of the myeloid lineage, have been reported to be closely related to the pathogenesis of tumour progression, but whether Neo can regulate MDSC expansion and function remains unclear. Here, we found that Neo could inhibit the expansion and suppressive function of MDSCs by targeting STAT3. Importantly, Neo inhibited the growth of 4T1 and LLC tumours in vivo, as well as lung metastasis of 4T1 tumours in vivo. Furthermore, we identified MDSCs as the direct targets by which Neo attenuated tumour progression. In addition, Neo notably enhanced anti-PD-1 efficacy in anti-PD-1-insensitive 4T1 tumours. Therefore, our study sheds light on the development of Neobased therapeutic strategies against cancer.
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Affiliation(s)
- Jufeng Guo
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yingying Shen
- Laboratory of Cancer Biology, The Key Lab of Biotherapy in Zhejiang Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310020, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Shufang Hu
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Tao Rui
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Jian Liu
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
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17
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Chen Y, Liu H, Zheng Q, Li H, You H, Feng Y, Feng W. Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin. Life Sci 2022; 306:120826. [PMID: 35870618 DOI: 10.1016/j.lfs.2022.120826] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/09/2022] [Accepted: 07/15/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND AND OBJECTIVES There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated. METHODS Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues. RESULTS The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells. CONCLUSIONS These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents. MAJOR FINDING This study observes a previously neglected pharmacological phenomenon and investigates its mechanism of that the continuous low-dose administration of some antineoplastic agents in certain dose ranges can promote tumorigenesis and tumor progression in vitro and in vivo, through stimulation of tumor cell functions directly as well as enhancement of tumor angiogenesis by BMDCs recruitment indirectly. The results alert to a potential risk in current empirically based continuous low-dose chemotherapy regimens such as metronomic chemotherapy.
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Affiliation(s)
- Yanshen Chen
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China; Department of Pharmacy, Jiangsu Vocational College of Medicine, Jiefang South Road 283 th, Yancheng 224005, Jiangsu, PR China
| | - Hua Liu
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Qiaowei Zheng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Houli Li
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Huining You
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Yan Feng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China
| | - Weiyi Feng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, Shaanxi, PR China.
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18
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Letchuman V, Ampie L, Shah AH, Brown DA, Heiss JD, Chittiboina P. Syngeneic murine glioblastoma models: reactionary immune changes and immunotherapy intervention outcomes. Neurosurg Focus 2022; 52:E5. [PMID: 35104794 PMCID: PMC10851929 DOI: 10.3171/2021.11.focus21556] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022]
Abstract
Glioblastoma is the most common primary malignant brain neoplasm with dismal 10-year survival rates of < 1%. Despite promising preliminary results from several novel therapeutic agents, clinical responses have been modest due to several factors, including tumor heterogeneity, immunosuppressive tumor microenvironment, and treatment resistance. Novel immunotherapeutics have been developed to reverse tumor-induced immunosuppression in patients with glioblastomas. In order to recapitulate the tumor microenvironment, reliable in vivo syngeneic murine models are critical for the development of new targeted agents as these models demonstrate rapid tumor induction and reliable tumor growth over multiple generations. Despite the clear advantages of murine models, choosing an appropriate model from an immunological perspective can be difficult and have significant ramifications on the translatability of the results from murine to human trials. Herein, the authors reviewed the 4 most commonly used immunocompetent syngeneic murine glioma models (GL261 [C57BL/6], SB28 [C57BL/6], CT-2A [C57BL/6], and SMA-560 [VM/Dk]) and compared their strengths and weaknesses from an immunological standpoint.
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Affiliation(s)
- Vijay Letchuman
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - Leonel Ampie
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Ashish H. Shah
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - Desmond A. Brown
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - John D. Heiss
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - Prashant Chittiboina
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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19
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Wang L, Hu D, Xie B, Xie L. Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells. Invest New Drugs 2022; 40:506-518. [PMID: 35089465 PMCID: PMC9098617 DOI: 10.1007/s10637-022-01218-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/21/2022] [Indexed: 01/04/2023]
Abstract
Background. In cancer, myeloid-derived suppressor cells (MDSCs) are known to escape the host immune system by developing a highly suppressive environment. However, little is known about the molecular mechanism behind MDSC-mediated tumor cell evasion of the immune system. Toll-like receptor (TLR) signaling elicited in the tumor microenvironment has the potential to induce MDSC differentiations in different organs. Therefore, MDSC elimination by blocking the action of myeloid differentiation factor 88 (MyD88), which is a key adaptor-signaling molecule that affects TLR activity, seems to be an ideal tumor immunotherapy. Previous studies have proven that blocking MyD88 signaling with a novel MyD88 inhibitor (TJ-M2010-5, synthesized by Zhou’s group) completely prevented colitis-associated colorectal cancer (CAC) development in mice. Methods. In the present study, we investigated the impact of the novel MyD88 inhibitor on the number, phenotype, and function of MDSC in the mice model of CAC. Results. We showed that CAC growth inhibition was involved in diminished MDSC generation, expansion, and suppressive function and that MDSC-mediated immune escape was dependent on MyD88 signaling pathway activation. MyD88 inhibitor treatment decreased the accumulation of CD11b+Gr1+ MDSCs in mice with CAC, thereby reducing cytokine (GM-CSF, G-CSF, IL-1β, IL-6 and TGF-β) secretion associated with MDSC accumulation, and reducing the expression of molecules (iNOS, Arg-1 and IDO) associated with the suppressive capacity of MDSCs. In addition, MyD88 inhibitor treatment reduced the differentiation of MDSCs from myeloid cells and the suppressive capacity of MDSCs on the proliferation of activated CD4+ T cells in vitro. Conclusion. MDSCs are primary cellular targets of a novel MyD88 inhibitor during CAC development. Our findings prove that MyD88 signaling is involved in the regulation of the immunosuppressive functions of MDSCs. The novel MyD88 inhibitor TJ-M2010-5 is a new and effective agent that modulates MyD88 signaling to overcome MDSC suppressive functions, enabling the development of successful antitumor immunotherapy.
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Affiliation(s)
- Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Dan Hu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bin Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lin Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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20
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microRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells. Int J Mol Sci 2022; 23:ijms23031275. [PMID: 35163198 PMCID: PMC8835847 DOI: 10.3390/ijms23031275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial-mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.
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Chen X, Zhang W, Yang W, Zhou M, Liu F. Acquired resistance for immune checkpoint inhibitors in cancer immunotherapy: challenges and prospects. Aging (Albany NY) 2022; 14:1048-1064. [PMID: 35037899 PMCID: PMC8833108 DOI: 10.18632/aging.203833] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 12/29/2021] [Indexed: 04/21/2023]
Abstract
Drug resistance has become an obstacle to the further development of immunotherapy in clinical applications and experimental studies. In the current review, the acquired resistance to immunotherapy was examined. The mechanisms of acquired resistance were based on three aspects as follows: The change of the tumor functions, the upregulated expression of inhibitory immune checkpoint proteins, and the effects of the tumor microenvironment. The combined use of immunotherapy and other therapies is performed to delay acquired resistance. A comprehensive understanding of acquired drug resistance may provide ideas for solving this dilemma.
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Affiliation(s)
- Xunrui Chen
- Department of Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
| | - Wenhui Zhang
- Shanghai Institute of Precision Medicine, Shanghai 200125, China
| | - Wenyan Yang
- Medical Center, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China
| | - Min Zhou
- Department of Respirtory Medicine, Jinshan Branch of the Sixth People’s Hospital of Shanghai, Shanghai 201599, P.R. China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
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22
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Wu L, Xu Y, Zhao H, Zhou Y, Chen Y, Yang S, Lei J, Zhang J, Wang J, Wu Y, Li Y. FcγRIIB potentiates differentiation of myeloid-derived suppressor cells to mediate tumor immunoescape. Am J Cancer Res 2022; 12:842-858. [PMID: 34976216 PMCID: PMC8692894 DOI: 10.7150/thno.66575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/22/2021] [Indexed: 11/05/2022] Open
Abstract
Background: FcγRIIB, the sole inhibitory receptor of the Fc gamma receptor family, plays pivotal roles in innate and adaptive immune responses. However, the expression and function of FcγRIIB in myeloid-derived suppressor cells (MDSCs) remains unknown. This study aimed to investigate whether and how FcγRIIB regulates the immunosuppressive activity of MDSCs during cancer development. Methods: The MC38 and B16-F10 tumor-bearing mouse models were established to investigate the role of FcγRIIB during tumor progression. FcγRIIB-deficient mice, adoptive cell transfer, mRNA-sequencing and flow cytometry analysis were used to assess the role of FcγRIIB on immunosuppressive activity and differentiation of MDSCs. Results: Here we show that FcγRIIB was upregulated in tumor-infiltrated MDSCs. FcγRIIB-deficient mice showed decreased accumulation of MDSCs in the tumor microenvironment (TME) compared with wild-type mice. FcγRIIB was required for the differentiation and immunosuppressive activity of MDSCs. Mechanistically, tumor cell-derived granulocyte-macrophage colony stimulating factor (GM-CSF) increased the expression of FcγRIIB on hematopoietic progenitor cells (HPCs) by activating specificity protein 1 (Sp1), subsequently FcγRIIB promoted the generation of MDSCs from HPCs via Stat3 signaling. Furthermore, blockade of Sp1 dampened MDSC differentiation and infiltration in the TME and enhanced the anti-tumor therapeutic efficacy of gemcitabine. Conclusion: These results uncover an unrecognized regulatory role of the FcγRIIB in abnormal differentiation of MDSCs during cancer development and suggest a potential therapeutic target for anti-tumor therapy.
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23
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Korbelik M, Szulc ZM, Bielawska A, Separovic D. Controlling Immunoregulatory Cell Activity for Effective Photodynamic Therapy of Cancer. Methods Mol Biol 2022; 2451:569-577. [PMID: 35505033 DOI: 10.1007/978-1-0716-2099-1_28] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Recently, it has become clear that a prerequisite requirement for most cancer therapies is controlling the negative impact of the activity of immunosuppressory cell populations. It is therefore of a considerable interest to develop treatments for containing the operation of major myeloid and lymphoid immunoregulatory cell populations. We have reported that acid ceramidase inhibitor LCL521 effectively overrides the activity of immunoregulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) engaged in the context of tumor response to photodynamic therapy (PDT). The present communication dissects and describes in detail the procedure for the use of LCL521 as an adjuvant to PDT for improved cure rates of treated tumors based on restricting the activity of immunoregulatory cell populations.
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Affiliation(s)
- Mladen Korbelik
- Department of Integrative Oncology, BC Cancer Research Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
| | - Zdzislaw M Szulc
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Alicja Bielawska
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Duska Separovic
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA
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24
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Liang J, Wang S, Zhang G, He B, Bie Q, Zhang B. A New Antitumor Direction: Tumor-Specific Endothelial Cells. Front Oncol 2021; 11:756334. [PMID: 34988011 PMCID: PMC8721012 DOI: 10.3389/fonc.2021.756334] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/25/2021] [Indexed: 12/19/2022] Open
Abstract
Targeting tumor blood vessels is an important strategy for tumor therapies. At present, antiangiogenic drugs are known to have significant clinical effects, but severe drug resistance and side effects also occur. Therefore, new specific targets for tumor and new treatment methods must be developed. Tumor-specific endothelial cells (TECs) are the main targets of antiangiogenic therapy. This review summarizes the differences between TECs and normal endothelial cells, assesses the heterogeneity of TECs, compares tumorigenesis and development between TECs and normal endothelial cells, and explains the interaction between TECs and the tumor microenvironment. A full and in-depth understanding of TECs may provide new insights for specific antitumor angiogenesis therapies.
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Affiliation(s)
- Jing Liang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Shouqi Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Guowei Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Baoyu He
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Qingli Bie
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, China
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25
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Qin M, Jin Y, Pan LY. Tertiary lymphoid structure and B-cell-related pathways: A potential target in tumor immunotherapy. Oncol Lett 2021; 22:836. [PMID: 34712360 PMCID: PMC8548801 DOI: 10.3892/ol.2021.13097] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/28/2021] [Indexed: 01/11/2023] Open
Abstract
The tertiary lymphoid structure (TLS), also referred to as the ectopic lymphoid structure, has recently become a focus of attention. The TLS consists of T-cell and B-cell-rich regions, as well as plasma cells, follicular helper T cells, follicular dendritic cells (FDCs), germinal centers (GCs) and high endothelial venules. TLSs can be divided into different subtypes and mature stages according to the density of FDCs and GCs. The TLS serves as an effective site in which an antitumor inflammatory response is generated through infiltrating immune cells. B-cell-related pathways, known as the CXC chemokine ligand 13/CXC chemokine receptor type 5 axis and the CC chemokine ligand (CCL)19/CCL21/CC-chemokine receptor 7 axis, play a key role in the generation and formation of TLSs. The aim of the present review was to systematically summarize updated research progress on the formation, subtypes, evaluation and B-cell-related pathways of TLSs. Furthermore, researchers have previously reported that TLSs are present in several types of solid cancers and that they are associated with survival outcomes. Therefore, studies on TLS in breast, lung, colorectal and ovarian cancers and melanoma were summarized and compared. The TLS and B-cell-related pathways require further investigation as important immune signals and promising new immunotherapy targets in the era of T-cell therapy revolution.
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Affiliation(s)
- Meng Qin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.,Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing 100730, P.R. China
| | - Ying Jin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.,Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing 100730, P.R. China
| | - Ling-Ya Pan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.,Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing 100730, P.R. China
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26
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Makaremi S, Asadzadeh Z, Hemmat N, Baghbanzadeh A, Sgambato A, Ghorbaninezhad F, Safarpour H, Argentiero A, Brunetti O, Bernardini R, Silvestris N, Baradaran B. Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects. Biomedicines 2021; 9:1075. [PMID: 34572263 PMCID: PMC8467932 DOI: 10.3390/biomedicines9091075] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy is a new pillar of cancer therapy that provides novel opportunities to treat solid tumors. In this context, the development of new drugs targeting immune checkpoints is considered a promising approach in colorectal cancer (CRC) treatment because it can be induce specific and durable anti-cancer effects. Despite many advances in the immunotherapy of CRC, there are still limitations and obstacles to successful treatment. The immunosuppressive function of the tumor microenvironment (TME) is one of the causes of poor response to treatment in CRC patients. For this reason, checkpoint-blocking antibodies have shown promising outcomes in CRC patients by blocking inhibitory immune checkpoints and enhancing immune responses against tumors. This review summarizes recent advances in immune checkpoint inhibitors (ICIs), such as CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 in CRC, and it discusses various therapeutic strategies with ICIs, including the double blockade of ICIs, combination therapy of ICIs with other immunotherapies, and conventional treatments. This review also delineates a new hopeful path in the combination of anti-PD-1/anti-PD-L1 with other ICIs such as anti-CTLA-4, anti-LAG-3, and anti-TIM-3 for CRC treatment.
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Affiliation(s)
- Shima Makaremi
- Department of Immunology & Microbiology, School of Medicine, Arak University of Medical Sciences, Arak 3848176941, Iran;
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran; (Z.A.); (N.H.); (A.B.); (F.G.)
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran; (Z.A.); (N.H.); (A.B.); (F.G.)
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran; (Z.A.); (N.H.); (A.B.); (F.G.)
| | - Alessandro Sgambato
- Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 5972362 Rome, Italy;
- Area of Pathology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 5972362 Rome, Italy
| | - Farid Ghorbaninezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran; (Z.A.); (N.H.); (A.B.); (F.G.)
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
| | - Hossein Safarpour
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand 9717853577, Iran;
| | - Antonella Argentiero
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy; (A.A.); (O.B.)
| | - Oronzo Brunetti
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy; (A.A.); (O.B.)
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95121 Catania, Italy;
| | - Nicola Silvestris
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy; (A.A.); (O.B.)
- Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, 70124 Bari, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran; (Z.A.); (N.H.); (A.B.); (F.G.)
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
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27
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Kapor S, Santibanez JF. Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies. J Clin Med 2021; 10:2788. [PMID: 34202907 PMCID: PMC8268878 DOI: 10.3390/jcm10132788] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/14/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022] Open
Abstract
Myeloid malignancies arise from an altered hematopoietic stem cell and mainly comprise acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic leukemic cells may influence the growth and differentiation of other hematopoietic cell lineages in peripheral blood and bone marrow. Myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs) display immunoregulatory properties by controlling the innate and adaptive immune systems that may induce a tolerant and supportive microenvironment for neoplasm development. This review analyzes the main features of MDSCs and MSCs in myeloid malignancies. The number of MDSCs is elevated in myeloid malignancies exhibiting high immunosuppressive capacities, whereas MSCs, in addition to their immunosuppression contribution, regulate myeloid leukemia cell proliferation, apoptosis, and chemotherapy resistance. Moreover, MSCs may promote MDSC expansion, which may mutually contribute to the creation of an immuno-tolerant neoplasm microenvironment. Understanding the implication of MDSCs and MSCs in myeloid malignancies may favor their potential use in immunotherapeutic strategies.
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Affiliation(s)
- Suncica Kapor
- Clinical Hospital Center “Dr Dragisa Misovic-Dedinje”, Department of Hematology, University of Belgrade, 11000 Belgrade, Serbia
| | - Juan F. Santibanez
- Molecular Oncology Group, Institute for Medical Research, University of Belgrade, 11000 Belgrade, Serbia;
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O’Higgins, 8370993 Santiago, Chile
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28
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Kapor S, Santibanez JF. Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies. J Clin Med 2021. [PMID: 34202907 DOI: 10.3390/jcm10132788.pmid:34202907;pmcid:pmc8268878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
Myeloid malignancies arise from an altered hematopoietic stem cell and mainly comprise acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic leukemic cells may influence the growth and differentiation of other hematopoietic cell lineages in peripheral blood and bone marrow. Myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs) display immunoregulatory properties by controlling the innate and adaptive immune systems that may induce a tolerant and supportive microenvironment for neoplasm development. This review analyzes the main features of MDSCs and MSCs in myeloid malignancies. The number of MDSCs is elevated in myeloid malignancies exhibiting high immunosuppressive capacities, whereas MSCs, in addition to their immunosuppression contribution, regulate myeloid leukemia cell proliferation, apoptosis, and chemotherapy resistance. Moreover, MSCs may promote MDSC expansion, which may mutually contribute to the creation of an immuno-tolerant neoplasm microenvironment. Understanding the implication of MDSCs and MSCs in myeloid malignancies may favor their potential use in immunotherapeutic strategies.
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Affiliation(s)
- Suncica Kapor
- Clinical Hospital Center "Dr Dragisa Misovic-Dedinje", Department of Hematology, University of Belgrade, 11000 Belgrade, Serbia
| | - Juan F Santibanez
- Molecular Oncology Group, Institute for Medical Research, University of Belgrade, 11000 Belgrade, Serbia
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, 8370993 Santiago, Chile
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Hu F, Liu J, Liu H, Li F, Wan M, Zhang M, Jiang Y, Rao M. Role of Exosomal Non-coding RNAs in Gastric Cancer: Biological Functions and Potential Clinical Applications. Front Oncol 2021; 11:700168. [PMID: 34195097 PMCID: PMC8238120 DOI: 10.3389/fonc.2021.700168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) is one of the most common fatal cancers worldwide. The communication between GC and other cells in the GC microenvironment directly affects GC progression. Recently, exosomes have been revealed as new players in intercellular communication. They play an important role in human health and diseases, including cancer, owing to their ability to carry various bioactive molecules, including non-coding RNAs (ncRNAs). NcRNAs, including micro RNAs, long non-coding RNAs, and circular RNAs, play a significant role in various pathophysiological processes, especially cancer. Increasing evidence has shown that exosomal ncRNAs are involved in the regulation of tumor proliferation, invasion, metastasis, angiogenesis, immune regulation, and treatment resistance in GC. In addition, exosomal ncRNAs have promising potential as diagnostic and prognostic markers for GC. Considering the biocompatibility of exosomes, they can also be used as biological carriers for targeted therapy. This review summarizes the current research progress on exosomal ncRNAs in gastric cancer, focusing on their biological role in GC and their potential as new biomarkers for GC and therapeutics. Our review provides insight into the mechanisms involved in GC progression, which may provide a new point cut for the discovery of new diagnostic markers and therapeutic strategies.
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Affiliation(s)
- Feng Hu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Jixuan Liu
- Department of Pathology, The First Hospital of Jilin University, Changchun, China
| | - Huibo Liu
- Department of Dermatology, The First Hospital of Jilin University, Changchun, China
| | - Fan Li
- Department of Anesthesia, The First Hospital of Jilin University, Changchun, China
| | - Minjie Wan
- Department of Central Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Manli Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yanfang Jiang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
| | - Min Rao
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models. Int J Mol Sci 2021; 22:ijms22115587. [PMID: 34070449 PMCID: PMC8197523 DOI: 10.3390/ijms22115587] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 05/21/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing syngeneic pancreatic (KCKO) or breast (C57MG) tumors. We observed enhanced tumor growth of pancreatic and breast tumors in the MUC1KO mice compared to the WT mice. Enhanced tumor growth in the MUC1KO mice was associated with increased numbers of suppressive MDSCs and T regulatory (Tregs) cells in the tumor microenvironment. Compared to the WT host, MUC1KO host showed higher levels of iNOS, ARG1, and TGF-β, thus promoting proliferation of MDSCs with an immature and immune suppressive phenotype. When co-cultured with effector T cells, MDSCs from MUC1KO mice led to higher repression of IL-2 and IFN-γ production by T cells as compared to MDSCs from WT mice. Lastly, MDSCs from MUC1KO mice showed higher levels of c-Myc and activated pSTAT3 as compared to MDSCs from WT mice, suggesting increased survival, proliferation, and prevention of maturation of MDSCs in the MUC1KO host. We report diminished T cell function in the KO versus WT mice. In summary, the data suggest that MUC1 may regulate signaling pathways that are critical to maintain the immunosuppressive properties of MDSCs.
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Huang Y, Yi T, Liu Y, Yan M, Peng X, Lv Y. The landscape of tumors-infiltrate immune cells in papillary thyroid carcinoma and its prognostic value. PeerJ 2021; 9:e11494. [PMID: 34055497 PMCID: PMC8142931 DOI: 10.7717/peerj.11494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/29/2021] [Indexed: 12/19/2022] Open
Abstract
Introduction Thyroid cancer is a very common malignant tumor in the endocrine system, while the incidence of papillary thyroid carcinoma (PTC) throughout the world also shows a trend of increase year by year. In this study, we constructed two models: ICIscore and Riskscore. Combined with these two models, we can make more accurate and reasonable inferences about the prognosis of PTC patients. Methods We selected 481 PTC samples from TCGA and 147 PTC samples from GEO (49 samples in GSE33630, 65 samples in GSE35570 and 33 samples in GSE60542). We performed consistent clustering for them and divided them into three subgroups and screened differentially expressed genes from these three subgroups. Then we divided the differential genes into three subtypes. We also distinguished the up-regulated and down-regulated genes and calculated ICIscore for each PTC sample. ICIscore consists of two parts: (1) the PCAu was calculated from up-regulated genes. (2) the PCAd was calculated from down-regulated genes. The PCAu and PCAd of each sample were the first principal component of the relevant gene. What’s more, we divided the patients into two groups and constructed mRNA prognostic signatures. Additionally we also verified the independent prognostic value of the signature. Results Though ICIscore, we were able to observe the relationship between immune infiltration and prognosis. The result suggests that the activation of the immune system may have both positive and negative consequences. Though Riskscore, we could make more accurate predictions about the prognosis of patients with PTC. Meanwhile, we also generated and validated the ICIscore group and Riskscore group respectively. Conclusion All the research results show that by combining the two models constructed, ICIscore and Riskscore, we can make a more accurate and reasonable inference about the prognosis of patients with clinical PTC patients. This suggests that we can provide more effective and reasonable treatment plan for clinical PTC patients.
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Affiliation(s)
- Yanyi Huang
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.,Nanchang University, The Second Clinical Medicine College, Nanchang, Jiangxi, China
| | - Tao Yi
- Department of Otolaryngology, People's Hospital of Yichun, Yichun, Jiangxi, China
| | - Yushu Liu
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.,Nanchang University, The Second Clinical Medicine College, Nanchang, Jiangxi, China
| | - Mengyun Yan
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.,Nanchang University, The First Clinical Medicine College, Nanchang, Jiangxi, China
| | - Xinli Peng
- Department of Otolaryngology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yunxia Lv
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Zalfa C, Paust S. Natural Killer Cell Interactions With Myeloid Derived Suppressor Cells in the Tumor Microenvironment and Implications for Cancer Immunotherapy. Front Immunol 2021; 12:633205. [PMID: 34025641 PMCID: PMC8133367 DOI: 10.3389/fimmu.2021.633205] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity. We also speculate on how NK cell-based antitumor immunotherapy could be improved.
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Affiliation(s)
| | - Silke Paust
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States
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Paston SJ, Brentville VA, Symonds P, Durrant LG. Cancer Vaccines, Adjuvants, and Delivery Systems. Front Immunol 2021; 12:627932. [PMID: 33859638 PMCID: PMC8042385 DOI: 10.3389/fimmu.2021.627932] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022] Open
Abstract
Vaccination was first pioneered in the 18th century by Edward Jenner and eventually led to the development of the smallpox vaccine and subsequently the eradication of smallpox. The impact of vaccination to prevent infectious diseases has been outstanding with many infections being prevented and a significant decrease in mortality worldwide. Cancer vaccines aim to clear active disease instead of aiming to prevent disease, the only exception being the recently approved vaccine that prevents cancers caused by the Human Papillomavirus. The development of therapeutic cancer vaccines has been disappointing with many early cancer vaccines that showed promise in preclinical models often failing to translate into efficacy in the clinic. In this review we provide an overview of the current vaccine platforms, adjuvants and delivery systems that are currently being investigated or have been approved. With the advent of immune checkpoint inhibitors, we also review the potential of these to be used with cancer vaccines to improve efficacy and help to overcome the immune suppressive tumor microenvironment.
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Affiliation(s)
| | | | - Peter Symonds
- Biodiscovery Institute, Scancell Limited, Nottingham, United Kingdom
| | - Lindy G. Durrant
- Biodiscovery Institute, University of Nottingham, Faculty of Medicine and Health Sciences, Nottingham, United Kingdom
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The Relationship between Hepatic Myeloid-Derived Suppressor Cells and Clinicopathological Parameters in Patients with Chronic Liver Disease. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6612477. [PMID: 33860040 PMCID: PMC8024072 DOI: 10.1155/2021/6612477] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/08/2021] [Accepted: 03/16/2021] [Indexed: 12/14/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) have attracted attention due to their important role in inflammation. Several studies have investigated the involvement of MDSCs in chronic liver disease. However, due to the difference of MDSC phenotypes, patient types, and sample sources among the studies, the results are inconsistent and controversial. We took advantage of a large well-defined cohort of 98 (24 patients with CHB, 18 with NAFLD, 13 with HCC, 16 with PBC, and 27 with AIH) patients with liver inflammation and 12 healthy controls to investigate the expression of MDSCs, and the relationships between the expression of hepatic MDSCs and the clinical characteristics were analyzed. We found that the expression of CD11b+CD33+ MDSCs is closely related to chronic liver disease and positively correlated with clinical parameters such as ALT, AST, and globulin. Ultimately, the present study suggests that hepatic CD11b+CD33+ MDSCs are increased in HCC and AIH and positively correlate with the liver stages of hepatitis activity and liver fibrosis stage.
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Ortiz-Cuaran S, Bouaoud J, Karabajakian A, Fayette J, Saintigny P. Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers. Front Oncol 2021; 11:614332. [PMID: 33718169 PMCID: PMC7947611 DOI: 10.3389/fonc.2021.614332] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/08/2021] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.
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Affiliation(s)
- Sandra Ortiz-Cuaran
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - Jebrane Bouaoud
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
- Department of Maxillofacial Surgery and Stomatology, Pitié-Salpêtrière University Hospital, Pierre et Marie Curie University, Sorbonne University, Paris, France
| | - Andy Karabajakian
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Jérôme Fayette
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Pierre Saintigny
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
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Lin L, Chen S, Wang H, Gao B, Kallakury B, Bhuvaneshwar K, Cahn K, Gusev Y, Wang X, Wu Y, Marshall JL, Zhi X, He AR. SPTBN1 inhibits inflammatory responses and hepatocarcinogenesis via the stabilization of SOCS1 and downregulation of p65 in hepatocellular carcinoma. Theranostics 2021; 11:4232-4250. [PMID: 33754058 PMCID: PMC7977457 DOI: 10.7150/thno.49819] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 12/07/2020] [Indexed: 12/31/2022] Open
Abstract
Background: Spectrin, beta, non-erythrocytic 1 (SPTBN1), an adapter protein for transforming growth factor beta (TGF-β) signaling, is recognized as a tumor suppressor in the development of hepatocellular carcinoma (HCC); however, the underlying molecular mechanisms of this tumor suppression remain obscure. Methods: The effects on expression of pro-inflammatory cytokines upon the inhibition or impairment of SPTBN1 in HCC cell lines and liver tissues of Sptbn1+/- and wild-type (WT) mice were assessed by analyses of quantitative real-time reverse-transcription polymerase chain reaction (QRT-PCR), enzyme linked immunosorbent assay (ELISA), Western blotting and gene array databases from HCC patients. We investigated the detailed molecular mechanisms underlying the inflammatory responses by immunoprecipitation-Western blotting, luciferase reporter assay, chromatin immunoprecipitation quantitative real time PCR (ChIP-qPCR), immunohistochemistry (IHC) and electrophoretic mobility shift assay (EMSA). The proportion of myeloid-derived suppressor cells in liver, spleen, bone marrow and peripheral blood samples from WT and Sptbn1+/- mice were measured by fluorescence-activated cell sorting (FACS) analysis. Further, the hepatocacinogenesis and its correlation with inflammatory microenvironment by loss of SPTBN1/SOCS1 and induction of p65 were analyzed by treating WT and Sptbn1+/- mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Results: Loss of SPTBN1 in HCC cells upregulated the expression of pro-inflammatory cytokines including interleukin-1α (IL-1α), IL-1β, and IL-6, and enhanced NF-κB transcriptional activation. Mechanistic analyses revealed that knockdown of SPTBN1 by siRNA downregulated the expression of suppressor of cytokine signaling 1 (SOCS1), an E3 ligase of p65, and subsequently upregulated p65 accumulation in the nucleus of HCC cells. Restoration of SOCS1 abrogated this SPTBN1 loss-associated elevation of p65 in HCC cells. In human HCC tissues, SPTBN1 gene expression was inversely correlated with gene expression of IL-1α, IL-1β and IL-6. Furthermore, a decrease in the levels of SPTBN1 gene, as well as an increase in the gene expression of IL-1β or IL-6 predicted shorter relapse free survival in HCC patients, and that HCC patients with low expression of SPTBN1 or SOCS1 protein is associated with poor survival. Heterozygous loss of SPTBN1 (Sptbn1+/-) in mice markedly upregulated hepatic expression of IL-1α, IL-1β and IL-6, and elevated the proportion of myeloid-derived suppressor cells (MDSCs) and CD4+CD25+Foxp3+ regulatory T cells (Foxp3+Treg) cells in the liver, promoting hepatocarcinogenesis of mouse fed by DDC. Conclusions: Our findings provided evidence that loss of SPTBN1 in HCC cells increases p65 protein stability via the inhibition of SOCS1 and enhances NF-κB activation, stimulating the release of inflammatory cytokines, which are critical molecular mechanisms for the loss of SPTBN1-induced liver cancer formation. Reduced SPTBN1 and SOCS1 predict poor outcome in HCC patients.
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Hu-Lieskovan S, Malouf GG, Jacobs I, Chou J, Liu L, Johnson ML. Addressing resistance to immune checkpoint inhibitor therapy: an urgent unmet need. Future Oncol 2021; 17:1401-1439. [PMID: 33475012 DOI: 10.2217/fon-2020-0967] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers by reversing the immunosuppressive mechanisms employed by tumors to restore anticancer immunity. Although ICIs have demonstrated substantial clinical efficacy, patient response can vary in depth and duration, and many do not respond at all or eventually develop resistance. ICI resistance mechanisms can be tumor-intrinsic, related to the tumor microenvironment or patient-specific factors. Multiple resistance mechanisms may be present within one tumor subtype, or heterogeneity exists among patients with the same tumor type. Consequently, designing effective combination treatment strategies is challenging. This review will discuss ICI resistance mechanisms, and summarize findings from key preclinical and clinical trials of ICIs, to identify potential treatment strategies or pathways to overcome ICI resistance.
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Affiliation(s)
- Siwen Hu-Lieskovan
- Department of Medicine, Division of Oncology, Huntsman Cancer Institute / University of Utah, Salt Lake City, UT 84112, USA
| | - Gabriel G Malouf
- Department of Medical Oncology, Institut de Cancérologie de Strasbourg & Department of Functional Genomics & Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, Illkirch Cedex, Strasbourg, France
| | | | | | - Li Liu
- Pfizer Inc, San Diego, CA 92121, USA
| | - Melissa L Johnson
- Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN 37203, USA
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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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Domagala M, Laplagne C, Leveque E, Laurent C, Fournié JJ, Espinosa E, Poupot M. Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells. Cancers (Basel) 2021; 13:E165. [PMID: 33418996 PMCID: PMC7825276 DOI: 10.3390/cancers13020165] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their individual roles in interaction between malignant cells, and the formation of the tumor microenvironment (TME). In this review, we focus on the myeloid cell compartment, a prominent, and heterogeneous group populating TME, which can initially exert an anti-tumoral effect, but with time actively participate in disease progression. Macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells, eosinophils, and basophils act alone or in concert to shape tumor cells resistance through cellular interaction and/or release of soluble factors favoring survival, proliferation, and migration of tumor cells, but also immune-escape and therapy resistance.
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Affiliation(s)
- Marcin Domagala
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Chloé Laplagne
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Edouard Leveque
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Camille Laurent
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
- IUCT-O, 31000 Toulouse, France
| | - Jean-Jacques Fournié
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Eric Espinosa
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Mary Poupot
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
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Mechanical strain induces phenotypic changes in breast cancer cells and promotes immunosuppression in the tumor microenvironment. J Transl Med 2020; 100:1503-1516. [PMID: 32572176 PMCID: PMC7686122 DOI: 10.1038/s41374-020-0452-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer (BCa) proliferates within a complex, three-dimensional microenvironment amid heterogeneous biochemical and biophysical cues. Understanding how mechanical forces within the tumor microenvironment (TME) regulate BCa phenotype is of great interest. We demonstrate that mechanical strain enhanced the proliferation and migration of both estrogen receptor+ and triple-negative (TNBC) human and mouse BCa cells. Furthermore, a critical role for exosomes derived from cells subjected to mechanical strain in these pro-tumorigenic effects was identified. Exosome production by TNBC cells increased upon exposure to oscillatory strain (OS), which correlated with elevated cell proliferation. Using a syngeneic, orthotopic mouse model of TNBC, we identified that preconditioning BCa cells with OS significantly increased tumor growth and myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the TME. This pro-tumorigenic myeloid cell enrichment also correlated with a decrease in CD8+ T cells. An increase in PD-L1+ exosome release from BCa cells following OS supported additive T cell inhibitory functions in the TME. The role of exosomes in MDSC and M2 macrophage was confirmed in vivo by cytotracking fluorescent exosomes, derived from labeled 4T1.2 cells, preconditioned with OS. In addition, in vivo internalization and intratumoral localization of tumor-cell derived exosomes was observed within MDSCs, M2 macrophages, and CD45-negative cell populations following direct injection of fluorescently-labeled exosomes. Our data demonstrate that exposure to mechanical strain promotes invasive and pro-tumorigenic phenotypes in BCa cells, indicating that mechanical strain can impact the growth and proliferation of cancer cell, alter exosome production by BCa, and induce immunosuppression in the TME by dampening anti-tumor immunity.
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Explicating the Pivotal Pathogenic, Diagnostic, and Therapeutic Biomarker Potentials of Myeloid-Derived Suppressor Cells in Glioblastoma. DISEASE MARKERS 2020; 2020:8844313. [PMID: 33204365 PMCID: PMC7657691 DOI: 10.1155/2020/8844313] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/19/2020] [Accepted: 10/24/2020] [Indexed: 11/17/2022]
Abstract
Glioblastoma (GBM) is a malignant and aggressive central nervous tumor that originates from astrocytes. These pathogenic astrocytes divide rapidly and are sustained by enormous network of blood vessels via which they receive requisite nutrients. It well proven that GBM microenvironment is extremely infiltrated by myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous cluster of immature myeloid progenitors. They are key mediates in immune suppression as well as sustenance glioma growth, invasion, vascularization, and upsurge of regulatory T cells via different molecules. MDSCs are often elevated in the peripheral blood of patients with GBM. MDSCs in the peripheral blood as well as those infiltrating the GBM microenvironment correlated with poor prognosis. Also, an upsurge in circulating MDSCs in the peripheral blood of patients with GBM was observed compared to benign and grade I/II glioma patients. GBM patients with good prognosis presented with reduced MDSCs as well as augmented dendritic cells. Almost all chemotherapeutic medication for GBM has shown no obvious improvement in overall survival in patients. Nevertheless, low-dose chemotherapies were capable of suppressing the levels of MDSCs in GBM as well as multiple tumor models with metastatic to the brain. Thus, MDSCs are potential diagnostic as well as therapeutic biomarkers for GBM patients.
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Safarzadeh E, Asadzadeh Z, Safaei S, Hatefi A, Derakhshani A, Giovannelli F, Brunetti O, Silvestris N, Baradaran B. MicroRNAs and lncRNAs-A New Layer of Myeloid-Derived Suppressor Cells Regulation. Front Immunol 2020; 11:572323. [PMID: 33133086 PMCID: PMC7562789 DOI: 10.3389/fimmu.2020.572323] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/28/2020] [Indexed: 12/23/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) constitute an important component in regulating immune responses in several abnormal physiological conditions such as cancer. Recently, novel regulatory tumor MDSC biology modulating mechanisms, including differentiation, expansion and function, were defined. There is growing evidence that miRNAs and long non-coding RNAs (lncRNA) are involved in modulating transcriptional factors to become complex regulatory networks that regulate the MDSCs in the tumor microenvironment. It is possible that aberrant expression of miRNAs and lncRNA contributes to MDSC biological characteristics under pathophysiological conditions. This review provides an overview on miRNAs and lncRNAs epiregulation of MDSCs development and immunosuppressive functions in cancer.
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Affiliation(s)
- Elham Safarzadeh
- Department of Microbiology & Immunology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Hatefi
- Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Medical Oncology Unit-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Francesco Giovannelli
- Medical Oncology Unit-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Nicola Silvestris
- Medical Oncology Unit-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Department of Internal Medicine and Oncology (DIMO)-University of Bari, Bari, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Dyer BA, Feng CH, Eskander R, Sharabi AB, Mell LK, McHale M, Mayadev JS. Current Status of Clinical Trials for Cervical and Uterine Cancer Using Immunotherapy Combined With Radiation. Int J Radiat Oncol Biol Phys 2020; 109:396-412. [PMID: 32942005 DOI: 10.1016/j.ijrobp.2020.09.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 09/04/2020] [Accepted: 09/08/2020] [Indexed: 01/05/2023]
Abstract
Novel therapies combined with radiation continue to be of significant interest in the developmental treatment paradigm of gynecologic cancers. Clinical implementation of immunotherapy in oncology has rapidly changed the treatment landscape, options, paradigm, and outcomes through clinical trials. Immunotherapy has emerged as a therapeutic pillar in the treatment of solid tumors with demonstrable synergistic activity when combined with radiation therapy and chemoradiotherapy by an alteration or enhancement of the immune system. In solid tumors, radiation therapy induces migration of dendritic cells, T cell activation, and proliferation, and increases in tumor-infiltrating lymphocytes. These immunomodulatory effects in conjunction with immune checkpoint blockade are currently under active investigation in the adjuvant, definitive, and metastatic settings. Results from early phase trials demonstrate promising efficacy and overall tolerable toxicity profiles of combined modality treatment. There is significant interest in optimizing the treatment for patients with locally advanced cervical cancer beyond the standard of care-chemoradiation-which has been in place for the last 30 years. The majority of cervical cancer emerges after persistent infection with a high-risk subtype of the human papillomavirus, where viral oncoproteins lead to cellular changes and immortalization. As a result, immune tolerance can develop, resulting in cancer. Knowledge of the mechanism of human papillomavirus-related oncogenesis suggests that immune therapy or checkpoint blockade can reinvigorate an antitumor immune response. Current clinical trials are exploring the therapeutic potential of these approaches. Uterine cancers have been grouped into 4 molecular subclasses by their driver mutations, mutational burden, and copy-number alterations. Of these subgroups, the polymerase epsilon-mutated and microsatellite-unstable may represent up to 40% of endometrial cancers, and they have been shown to be immunogenic. Because of the inherent immunogenicity of these MSI-high tumors, combined immune modulation strategies, including chemotherapy, radiation, and immunotherapy and immune checkpoint inhibitor therapy, are being explored to improve treatment outcomes. In this review, we explore current immunomodulatory and multimodality therapeutic approaches in the treatment of cervical and uterine cancer through ongoing clinical trials investigating the combination of immunotherapy and radiation therapy.
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Affiliation(s)
- Brandon A Dyer
- Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington
| | - Christine H Feng
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California
| | - Ramez Eskander
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Services, University of California San Diego, La Jolla, California
| | - Andrew B Sharabi
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California
| | - Loren K Mell
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California
| | - Michael McHale
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Services, University of California San Diego, La Jolla, California
| | - Jyoti S Mayadev
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.
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Wang Z, Wu X. Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker. Cancer Med 2020; 9:8086-8121. [PMID: 32875727 PMCID: PMC7643687 DOI: 10.1002/cam4.3410] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.
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Affiliation(s)
- Zhengyi Wang
- GCP Center of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital Medical Sciences, Chengdu City, Sichuan Province, China.,Institute of Laboratory Animals of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu City, Sichuan Province, China
| | - Xiaoying Wu
- Ministry of Education and Training, Second People's Hospital, Chengdu City, Sichuan Province, China
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Pan X, Zheng L. Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment. Cell Mol Immunol 2020; 17:940-953. [PMID: 32699350 PMCID: PMC7609272 DOI: 10.1038/s41423-020-0505-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open
Abstract
Epigenetic regulation of gene expression in cancer cells has been extensively studied in recent decades, resulting in the FDA approval of multiple epigenetic agents for treating different cancer types. Recent studies have revealed novel roles of epigenetic dysregulation in altering the phenotypes of immune cells and tumor-associated stromal cells, including fibroblasts and endothelial cells. As a result, epigenetic dysregulation of these cells reshapes the tumor microenvironment (TME), changing it from an antitumor environment to an immunosuppressive environment. Here, we review recent studies demonstrating how specific epigenetic mechanisms drive aspects of stromal and immune cell differentiation with implications for the development of solid tumor therapeutics, focusing on the pancreatic ductal adenocarcinoma (PDA) TME as a representative of solid tumors. Due to their unique ability to reprogram the TME into a more immunopermissive environment, epigenetic agents have great potential for sensitizing cancer immunotherapy to augment the antitumor response, as an immunopermissive TME is a prerequisite for the success of cancer immunotherapy but is often not developed with solid tumors. The idea of combining epigenetic agents with cancer immunotherapy has been tested both in preclinical settings and in multiple clinical trials. In this review, we highlight the basic biological mechanisms underlying the synergy between epigenetic therapy and immunotherapy and discuss current efforts to translate this knowledge into clinical benefits for patients.
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Affiliation(s)
- Xingyi Pan
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Cellular & Molecular Medicine Graduate Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Cellular & Molecular Medicine Graduate Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Saleh R, Taha RZ, Sasidharan Nair V, Toor SM, Alajez NM, Elkord E. Transcriptomic Profiling of Circulating HLA-DR - Myeloid Cells, Compared with HLA-DR + Myeloid Antigen-presenting Cells. Immunol Invest 2020; 50:952-963. [PMID: 32727251 DOI: 10.1080/08820139.2020.1795875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with potent immunosuppressive functions, which can inhibit the activation of immune responses under a steady-state condition and pathological conditions. We performed transcriptomic profiling of circulating CD33+HLA-DR+ myeloid antigen-presenting cells (APCs) and CD33+HLA-DR- myeloid cells (potentially MDSCs) in healthy individuals. We sorted both subpopulations from peripheral blood mononuclear cells (PBMCs) of 10 healthy donors and performed RNA sequencing (RNA-Seq). We found that several signaling pathways associated with the positive regulation of immune responses, such as antigen presentation/processing, FcγR-mediated phagocytosis and immune cell trafficking, phosphoinositide 3-kinase (PI3K)/Akt signaling, DC maturation, triggering receptor expressed on myeloid cells 1 (TREM1) signaling, nuclear factor of activated T cells (NFAT) and IL-8 signaling were downregulated in CD33+HLA-DR- myeloid cells. In contrast, pathways implicated in tumor suppression and anti-inflammation, including peroxisome proliferator-activated receptor (PPAR) and phosphatase and tensin homolog (PTEN), were upregulated in CD33+HLA-DR- myeloid cells. These data indicate that PPAR/PTEN axis could be upregulated in myeloid cells to keep the immune system in check in normal physiological conditions. Our data reveal some of the molecular and functional differences between CD33+HLA-DR+ APCs and CD33+HLA-DR- myeloid cells in a steady-state condition, reflecting the potential suppressive function of CD33+HLA-DR- myeloid cells to maintain immune tolerance. For future studies, the same methodological approach could be applied to perform transcriptomic profiling of myeloid subsets in pathological conditions.
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Affiliation(s)
- Reem Saleh
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Rowaida Z Taha
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Varun Sasidharan Nair
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Salman M Toor
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Nehad M Alajez
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Eyad Elkord
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
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48
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De Cicco P, Ercolano G, Ianaro A. The New Era of Cancer Immunotherapy: Targeting Myeloid-Derived Suppressor Cells to Overcome Immune Evasion. Front Immunol 2020; 11:1680. [PMID: 32849585 PMCID: PMC7406792 DOI: 10.3389/fimmu.2020.01680] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 06/23/2020] [Indexed: 12/24/2022] Open
Abstract
Suppression of antitumor immune responses is one of the main mechanisms by which tumor cells escape from destruction by the immune system. Myeloid-derived suppressor cells (MDSCs) represent the main immunosuppressive cells present in the tumor microenvironment (TME) that sustain cancer progression. MDSCs are a heterogeneous group of immature myeloid cells with a potent activity against T-cell. Studies in mice have demonstrated that MDSCs accumulate in several types of cancer where they promote invasion, angiogenesis, and metastasis formation and inhibit antitumor immunity. In addition, different clinical studies have shown that MDSCs levels in the peripheral blood of cancer patients correlates with tumor burden, stage and with poor prognosis in multiple malignancies. Thus, MDSCs are the major obstacle to many cancer immunotherapies and their targeting may be a beneficial strategy for improvement the efficiency of immunotherapeutic interventions. However, the great heterogeneity of these cells makes their identification in human cancer very challenging. Since both the phenotype and mechanisms of action of MDSCs appear to be tumor-dependent, it is important to accurately characterized the precise MDSC subsets that have clinical relevance in each tumor environment to more efficiently target them. In this review we summarize the phenotype and the suppressive mechanisms of MDSCs populations expanded within different tumor contexts. Further, we discuss about their clinical relevance for cancer diagnosis and therapy.
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Affiliation(s)
- Paola De Cicco
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giuseppe Ercolano
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.,Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Lausanne, Switzerland
| | - Angela Ianaro
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
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Jiang Z, Hsu JL, Li Y, Hortobagyi GN, Hung MC. Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment. Front Oncol 2020; 10:1197. [PMID: 32775303 PMCID: PMC7387712 DOI: 10.3389/fonc.2020.01197] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/12/2020] [Indexed: 12/16/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.
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Affiliation(s)
- Zhou Jiang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jennifer L. Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yintao Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Gabriel N. Hortobagyi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Center for Molecular Medicine and Research Center for Cancer Biology, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
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50
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Dal Bo M, De Mattia E, Baboci L, Mezzalira S, Cecchin E, Assaraf YG, Toffoli G. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma. Drug Resist Updat 2020; 51:100702. [DOI: 10.1016/j.drup.2020.100702] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/06/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
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