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1
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Issa H, Singh L, Lai KS, Parusheva-Borsitzky T, Ansari S. Dynamics of inflammatory signals within the tumor microenvironment. World J Exp Med 2025; 15:102285. [DOI: 10.5493/wjem.v15.i2.102285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/31/2024] [Accepted: 01/11/2025] [Indexed: 04/16/2025] Open
Abstract
Tumor stroma, or tumor microenvironment (TME), has been in the spotlight during recent years for its role in tumor development, growth, and metastasis. It consists of a myriad of elements, including tumor-associated macrophages, cancer-associated fibroblasts, a deregulated extracellular matrix, endothelial cells, and vascular vessels. The release of proinflammatory molecules, due to the inflamed microenvironment, such as cytokines and chemokines is found to play a pivotal role in progression of cancer and response to therapy. This review discusses the major key players and important chemical inflammatory signals released in the TME. Furthermore, the latest breakthroughs in cytokine-mediated crosstalk between immune cells and cancer cells have been highlighted. In addition, recent updates on alterations in cytokine signaling between chronic inflammation and malignant TME have also been reviewed.
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Affiliation(s)
- Hala Issa
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
| | - Lokjan Singh
- Department of Microbiology, Karnali Academy of Health Sciences, Jumla 21200, Karnali, Nepal
| | - Kok-Song Lai
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
| | - Tina Parusheva-Borsitzky
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
| | - Shamshul Ansari
- Division of Health Sciences, Higher Colleges of Technology, Abu Dhabi 25026, United Arab Emirates
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2
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Tulsian K, Thakker D, Vyas VK. Overcoming chimeric antigen receptor-T (CAR-T) resistance with checkpoint inhibitors: Existing methods, challenges, clinical success, and future prospects : A comprehensive review. Int J Biol Macromol 2025; 306:141364. [PMID: 39988153 DOI: 10.1016/j.ijbiomac.2025.141364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/20/2024] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
Immune checkpoint blockade is, as of today, the most successful form of cancer immunotherapy, with more than 43 % of cancer patients in the US eligible to receive it; however, only up to 12.5 % of patients respond to it. Similarly, adoptive cell therapy using bioengineered chimeric antigen receptorT (CAR-T) cells and T-cell receptor (TCR) cells has provided excellent responses against liquid tumours, but both forms of immunotherapy have encountered challenges within a tumour microenvironment that is both lacking in tumour-specific T-cells and is strongly immunosuppressive toward externally administered CAR-T and TCR cells. This review focuses on understanding approved checkpoint blockade and adoptive cell therapy at both biological and clinical levels before delving into how and why their combination holds significant promise in overcoming their individual shortcomings. The advent of next-generation checkpoint inhibitors has further strengthened the immune checkpoint field, and a special section explores how these inhibitors can address existing hurdles in combining checkpoint blockade with adoptive cell therapy and homing in on our cancer target for long-term immunity.
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Affiliation(s)
- Kartik Tulsian
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India
| | - Dhinal Thakker
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India
| | - Vivek K Vyas
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382481, Gujarat, India.
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Chen R, Zhang R, Ke F, Guo X, Zeng F, Liu Q. Mechanisms of breast cancer metastasis: the role of extracellular matrix. Mol Cell Biochem 2025; 480:2771-2796. [PMID: 39652293 DOI: 10.1007/s11010-024-05175-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/23/2024] [Indexed: 05/03/2025]
Abstract
The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.
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Affiliation(s)
- Rui Chen
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
| | - Ranqi Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China
| | - Famin Ke
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xiurong Guo
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Fancai Zeng
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China.
| | - Qiuyu Liu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Laboratory of Biochemistry and Molecular Biology, School of Basic Medical Science, Southwest Medical University, Luzhou, 646000, China.
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Ke TW, Chen CY, Chen WTL, Tsai YY, Chiang SF, Huang CH, Lin YS, Chen TH, Chen TW, Liang JA, Chao KSC, Huang KCY. Targeting B7-H3 enhances the efficacy of neoantigen-based cancer vaccine in combination with radiotherapy. NPJ Vaccines 2025; 10:80. [PMID: 40258806 PMCID: PMC12012209 DOI: 10.1038/s41541-025-01132-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 04/07/2025] [Indexed: 04/23/2025] Open
Abstract
The clinical response to immune checkpoint blockade (ICB) is limited in the majority of patients with colorectal cancer. These immune checkpoint proteins may not only inhibit T-cell-mediated antitumor immunity but also attenuate antigen presentation, including mutation-associated neoantigens. Here, we found that tumor B7-H3 levels may limit the therapeutic response to chemoradiotherapy in patients with locally-advanced rectal cancer. Knockdown of tumor B7-H3 significantly increased antigen presentation to increase T cell infiltration and killing ability, including neoantigen-specific T-cell response. Blockade of B7-H3 significantly augmented neoantigen-specific T cells response and remarkably enhanced the therapeutic efficacy of neoantigen-based cancer vaccines combined with radiotherapy, decreasing the risk of distant tumors in vivo. Taken together, these results demonstrated that targeting B7-H3 significantly enhanced the therapeutic efficacy of neoantigen cancer vaccines as well as radiotherapy by increasing the extent of neoantigen-specific T cells, even for PD-1/PD-L1 blockade-resistant colorectal cancers.
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Affiliation(s)
- Tao-Wei Ke
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan
- School of Chinese Medicine & Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chia-Yi Chen
- Proton Therapy Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - William Tzu-Liang Chen
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, Taiwan
| | - Yuan-Yao Tsai
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Shu-Fen Chiang
- Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan
| | - Chi-Hsien Huang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Yu-Sen Lin
- Department of Chest Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Te-Hong Chen
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Tsung-Wei Chen
- Department of Pathology, Asia University Hospital, Asia University, Taichung, Taiwan
| | - Ji-An Liang
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung, Taiwan
| | - K S Clifford Chao
- Proton Therapy Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Kevin Chih-Yang Huang
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan.
- Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan.
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Dai X, Cao B, Liu X, Meng W, Qiu Y, Sun Y, Zhang L, Li N, Liu Z, Li D, Xiao L, Li B, Zhang Q. Tumor vascular normalization by B7-H3 blockade augments T lymphocyte-mediated antitumor immunity. Eur J Pharmacol 2025; 993:177334. [PMID: 39892447 DOI: 10.1016/j.ejphar.2025.177334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 01/09/2025] [Accepted: 01/30/2025] [Indexed: 02/03/2025]
Abstract
Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), presents unique clinical challenges and generally predicts a less favorable prognosis. Despite recent advancements in TNBC treatment, a subset of patients remains resistant to immunotherapy. B7-H3, a member of the B7 family of immune checkpoints, is correlated with poor outcomes in various cancers and is distinctively expressed in tumor vasculature, marking it as a potential biomarker for tumor-associated endothelial cells. We found high expression of B7-H3 in the endothelial cells of the postoperative tissue of TNBC patients. Elevated gene expression of CD276 (encoding B7-H3) and PECAM1 (encoding CD31) in TNBC is associated with poor prognosis. Anti-B7-H3 blockade reduces tumor burden and promotes lymphocyte infiltration in a TNBC mouse model. Additionally, anti-B7-H3 blockade promotes tumor vessel normalization and enhances programmed cell death ligand 1 (PD-L1) expression. Synergistic effects were observed when B7-H3 blockade was combined with programmed cell death protein 1 (PD-1) inhibition in the TNBC mouse model. Furthermore, anti-B7-H3 inhibits human umbilical vein endothelial cell (HUVEC) proliferation by suppression of the nuclear factor kappa-B (NF-κB) signaling pathway. Downregulation of B7-H3 expression in HUVECs promotes lymphocyte trans-endothelial migration. These findings suggest that B7-H3 represents a promising therapeutic target for TNBC, and the combination of anti-B7-H3 and anti-PD-1 therapies may have synergetic effects in treating TNBC.
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Affiliation(s)
- Xin Dai
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China; Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Boran Cao
- Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinnan Liu
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wangyang Meng
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiran Qiu
- Department of Breast Surgery, Obstetrics and Gynecology Hospital, Fudan University School of Medicine, Shanghai, China
| | - Yidan Sun
- Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lulu Zhang
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Nan Li
- Department of Pathology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhenyu Liu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dan Li
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lianbo Xiao
- Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Bin Li
- Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qingyuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
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Jiang Y, Qian Z, Wang C, Wu D, Liu L, Ning X, You Y, Mei J, Zhao X, Zhang Y. Targeting B7-H3 inhibition-induced activation of fatty acid synthesis boosts anti-B7-H3 immunotherapy in triple-negative breast cancer. J Immunother Cancer 2025; 13:e010924. [PMID: 40221152 PMCID: PMC11997833 DOI: 10.1136/jitc-2024-010924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is the most malignant breast cancer, highlighting the need for effective immunotherapeutic targets. The immune checkpoint molecule B7-H3 has recently gained attention as a promising therapeutic target due to its pivotal role in promoting tumorigenesis and cancer progression. However, the therapeutic impact of B7-H3 inhibitors (B7-H3i) remains unclear. METHODS Transcriptomic and metabolomic analyses were conducted to explore the underlying mechanisms of B7-H3 inhibition in TNBC. The therapeutic efficacy of the combined treatment strategy was substantiated through comprehensive phenotypic assays conducted in vitro and validated in vivo using animal models. RESULTS B7-H3 blockade induces a "primed for death" stress state in cancer cells, leading to distinct alterations in metabolic pathways. Specifically, B7-H3 knockdown activated the AKT signaling pathway and upregulated sterol regulatory element-binding protein 1 (SREBP1), which in turn elevated FASN expression. The simultaneous inhibition of both B7-H3 and FASN more effectively attenuated the malignant progression of TNBC. CONCLUSIONS Our findings propose an "immune attack-metabolic compensation" dynamic model and suggest the feasibility of a dual-targeting strategy that concurrently inhibits both B7-H3 and FASN to enhance therapeutic efficacy in TNBC patients.
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Affiliation(s)
- Ying Jiang
- Department of Oncology, Women's Hospital of Jiangnan University, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhiwen Qian
- Department of Oncology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Cenzhu Wang
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Danping Wu
- Department of Oncology, Women's Hospital of Jiangnan University, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Lu Liu
- Department of Oncology, Women's Hospital of Jiangnan University, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xin Ning
- Department of Oncology, Women's Hospital of Jiangnan University, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yilan You
- Department of Oncology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Mei
- The First Clinical Medicine College, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoqian Zhao
- Department of Breast Surgery, Women's Hospital of Jiangnan University, Wuxi, China
| | - Yan Zhang
- Department of Oncology, Women's Hospital of Jiangnan University, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Department of Oncology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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Jin H, Meng X, Feng J. Mechanisms of tumor-associated macrophages in breast cancer and treatment strategy. Front Immunol 2025; 16:1560393. [PMID: 40092996 PMCID: PMC11906463 DOI: 10.3389/fimmu.2025.1560393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Breast cancer (BC) is the most common cancer in women and a leading cause of cancer-related mortality. Despite advances in screening and treatment, outcomes for advanced or recurrent BC remain poor, highlighting the need for new strategies. Recent research emphasizes the tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), as key drivers of tumor growth, metastasis, and resistance to therapy. The presence of M2-like TAMs in the TME promotes immune evasion and tumor progression across BC subtypes. This review summarizes TAMs classification, their role in BC, and emerging therapies targeting TAMs, including depletion, inhibition of recruitment, and reprogramming from pro-tumoral M2 to anti-tumoral M1 phenotypes. Targeting TAMs offers a promising strategy to improve BC treatment outcomes.
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Affiliation(s)
| | - Xinyue Meng
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianwei Feng
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Nedeljković M, Vuletić A, Mirjačić Martinović K. Divide and Conquer-Targeted Therapy for Triple-Negative Breast Cancer. Int J Mol Sci 2025; 26:1396. [PMID: 40003864 PMCID: PMC11855393 DOI: 10.3390/ijms26041396] [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: 12/16/2024] [Revised: 01/31/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive and malignant type of breast cancer with limited treatment options and poor prognosis. One of the most significant impediments in TNBC treatment is the high heterogeneity of this disease, as highlighted by the detection of several molecular subtypes of TNBC. Each subtype is driven by distinct mutations and pathway aberrations, giving rise to specific molecular characteristics closely connected to clinical behavior, outcomes, and drug sensitivity. This review summarizes the knowledge regarding TNBC molecular subtypes and how it can be harnessed to devise tailored treatment strategies instead of blindly using targeted drugs. We provide an overview of novel targeted agents and key insights about new treatment modalities with an emphasis on the androgen receptor signaling pathway, cancer stem cell-associated pathways, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, growth factor signaling, and immunotherapy.
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Affiliation(s)
- Milica Nedeljković
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.V.); (K.M.M.)
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Sang M, Ge J, Ge J, Tang G, Wang Q, Wu J, Mao L, Ding X, Zhou X. Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes. Front Immunol 2025; 15:1382842. [PMID: 39911580 PMCID: PMC11794490 DOI: 10.3389/fimmu.2024.1382842] [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: 02/06/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025] Open
Abstract
Background and aims Immunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood. Methods Data for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry. Results We were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors. Conclusion In this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy.
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Affiliation(s)
- Mengmeng Sang
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Jia Ge
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Juan Ge
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
- Department of Respiratory Medicine, Affiliated Nantong Hospital of Shanghai University, Nantong, China
| | - Gu Tang
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Qiwen Wang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiarun Wu
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Liming Mao
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China
| | - Xiaoling Ding
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiaorong Zhou
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
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Naji O, Ghouzlani A, Rafii S, Sadiqi RU, Kone AS, Harmak Z, Choukri K, Kandoussi S, Karkouri M, Badou A. Investigating tumor immunogenicity in breast cancer: deciphering the tumor immune response to enhance therapeutic approaches. Front Immunol 2024; 15:1399754. [PMID: 39507526 PMCID: PMC11538072 DOI: 10.3389/fimmu.2024.1399754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 09/18/2024] [Indexed: 11/08/2024] Open
Abstract
The interplay between immune cells and malignant cells represents an essential chapter in the eradication of breast cancer. This widely distributed and diverse form of cancer represents a major threat to women worldwide. The incidence of breast cancer is related to several risk factors, notably genetic predisposition and family antecedents. Despite progress in treatment modalities varying from surgery and chemotherapy to radiotherapy and targeted therapies, persistently high rates of recurrence, metastasis, and treatment resistance underscore the urgent need for new therapeutic approaches. Immunotherapy has gained considerable ground in the treatment of breast cancer, as it takes advantage of the complex interactions within the tumor microenvironment. This dynamic interplay between immune and tumor cells has become a key point of focus in immunological research. This study investigates the role of various cancer markers, such as neoantigens and immune regulatory genes, in the diagnosis and treatment of breast tumors. Moreover, it explores the future potential of immune checkpoint inhibitors as therapeutically effective agents, as well as the challenges that prevent their efficacy, in particular tumor-induced immunosuppression and the difficulty of achieving tumor specificity.
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Affiliation(s)
- Oumayma Naji
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Soumaya Rafii
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Rizwan ullah Sadiqi
- Faculty of Science and Technology, Middlesex University, London, United Kingdom
| | - Abdou-samad Kone
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Zakia Harmak
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Khalil Choukri
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Sarah Kandoussi
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Mehdi Karkouri
- Department of Pathological Anatomy, University Hospital Center (CHU) Ibn Rochd and Faculty of Medicine and Pharmacy of Casablanca, Hassan II University, Casablanca, Morocco
| | - Abdallah Badou
- Immuno-Genetics and Human Pathologies Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
- Mohammed VI Center for Research and Innovation, Rabat and Mohammed VI University for Sciences and Health, Casablanca, Morocco
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11
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Yu M, Yu H, Wang H, Xu X, Sun Z, Chen W, Yu M, Liu C, Jiang M, Zhang X. Tumor‑associated macrophages activated in the tumor environment of hepatocellular carcinoma: Characterization and treatment (Review). Int J Oncol 2024; 65:100. [PMID: 39239752 PMCID: PMC11387121 DOI: 10.3892/ijo.2024.5688] [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: 05/09/2024] [Accepted: 08/08/2024] [Indexed: 09/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) tissue is rich in dendritic cells, T cells, B cells, macrophages, natural killer cells and cellular stroma. Together they form the tumor microenvironment (TME), which is also rich in numerous cytokines. Tumor‑associated macrophages (TAMs) are involved in the regulation of tumor development. TAMs in HCC receive stimuli in different directions, polarize in different directions and release different cytokines to regulate the development of HCC. TAMs are mostly divided into two cell phenotypes: M1 and M2. M1 TAMs secrete pro‑inflammatory mediators, and M2 TAMs secrete a variety of anti‑inflammatory and pro‑tumorigenic substances. The TAM polarization in HCC tumors is M2. Both direct and indirect methods for TAMs to regulate the development of HCC are discussed. TAMs indirectly support HCC development by promoting peripheral angiogenesis and regulating the immune microenvironment of the TME. In terms of the direct regulation between TAMs and HCC cells, the present review mainly focuses on the molecular mechanism. TAMs are involved in both the proliferation and apoptosis of HCC cells to regulate the quantitative changes of HCC, and stimulate the related invasive migratory ability and cell stemness of HCC cells. The present review aims to identify immunotherapeutic options based on the mechanisms of TAMs in the TME of HCC.
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Affiliation(s)
- Mingkai Yu
- School of Clinical Medicine and Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Haixia Yu
- Pharmacy College, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Hongmei Wang
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Xiaoya Xu
- School of Clinical Medicine and Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Zhaoqing Sun
- School of Clinical Medicine and Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Wenshuai Chen
- School of Clinical Medicine and Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Miaomiao Yu
- School of Clinical Medicine and Basic Medical Science, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Chunhua Liu
- Department of Physiology and Neurobiology, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Mingchun Jiang
- Department of Physiology and Neurobiology, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250000, P.R. China
| | - Xiaowei Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, P.R. China
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12
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de Matos Rodrigues J, Lokhande L, Olsson LM, Hassan M, Johansson A, Janská A, Kumar D, Schmidt L, Nikkarinen A, Hollander P, Glimelius I, Porwit A, Gerdtsson AS, Jerkeman M, Ek S. CD163+ macrophages in mantle cell lymphoma induce activation of prosurvival pathways and immune suppression. Blood Adv 2024; 8:4370-4385. [PMID: 38959399 PMCID: PMC11375268 DOI: 10.1182/bloodadvances.2023012039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024] Open
Abstract
ABSTRACT Mantle cell lymphoma (MCL) is dependent on a supportive tumor immune microenvironment (TIME) in which infiltration of CD163+ macrophages has a negative prognostic impact. This study explores how abundance and spatial localization of CD163+ cells are associated with the biology of MCL, using spatial multiomic investigations of tumor and infiltrating CD163+ and CD3+ cells. A total of 63 proteins were measured using GeoMx digital spatial profiling in tissue microarrays from 100 diagnostic MCL tissues. Regions of interest were selected in tumor-rich and tumor-sparse tissue regions. Molecular profiling of CD163+ macrophages, CD20+ MCL cells, and CD3+ T-cells was performed. To validate protein profiles, 1811 messenger RNAs were measured in CD20+ cells and 2 subsets of T cells. Image analysis was used to extract the phenotype and position of each targeted cell, thereby allowing the exploration of cell frequencies and cellular neighborhoods. Proteomic investigations revealed that CD163+ cells modulate their immune profile depending on their localization and that the immune inhibitory molecules, V-domain immunoglobulin suppressor of T-cell activation and B7 homolog 3, have higher expression in tumor-sparse than in tumor-rich tissue regions and that targeting should be explored. We showed that MCL tissues with more abundant infiltration of CD163+ cells have a higher proteomic and transcriptional expression of key components of the MAPK pathway. Thus, the MAPK pathway may be a feasible therapeutic target in patients with MCL with CD163+ cell infiltration. We further showed the independent and combined prognostic values of CD11c and CD163 beyond established risk factors.
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Affiliation(s)
| | | | - Lina M. Olsson
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - May Hassan
- Department of Immunotechnology, Lund University, Lund, Sweden
| | | | - Anna Janská
- Department of Immunotechnology, Lund University, Lund, Sweden
| | | | - Lina Schmidt
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Anna Nikkarinen
- Department of Immunology, Genetics and Pathology, Cancer Precision Medicine, Uppsala University, Uppsala, Sweden
| | - Peter Hollander
- Department of Immunology, Genetics and Pathology, Clinical and Experimental Pathology, Uppsala University, Uppsala, Sweden
| | - Ingrid Glimelius
- Department of Immunology, Genetics and Pathology, Cancer Precision Medicine, Uppsala University, Uppsala, Sweden
| | - Anna Porwit
- Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | | | - Mats Jerkeman
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Sara Ek
- Department of Immunotechnology, Lund University, Lund, Sweden
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13
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Park R, Yu J, Shahzad M, Lee S, Ji JD. The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages. Immunol Res 2024; 72:526-537. [PMID: 38265550 DOI: 10.1007/s12026-024-09458-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/17/2024] [Indexed: 01/25/2024]
Abstract
B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.
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Affiliation(s)
- Robin Park
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - James Yu
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - Moazzam Shahzad
- Department of Hematology/Oncology, Moffitt Cancer Center/University of South Florida, Tampa, FL, USA
| | - Sunggon Lee
- Department of Internal Medicine, Korea University, Seoul, South Korea
| | - Jong Dae Ji
- Department of Rheumatology, College of Medicine, Korea University, Seoul, South Korea.
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14
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Sun L, Rao S, Kerim K, Lu J, Li H, Zhao S, Shen P, Sun W. A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation. Biochem Pharmacol 2024; 225:116262. [PMID: 38705535 DOI: 10.1016/j.bcp.2024.116262] [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: 12/08/2023] [Revised: 04/29/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.
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Affiliation(s)
- Luchen Sun
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Shangrui Rao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Kamran Kerim
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Jianhua Lu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Hongzheng Li
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Shengsheng Zhao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Pingping Shen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Shenzhen Research Institute of NanJing University, Shenzhen 518000, China.
| | - Weijian Sun
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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15
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Wu S, Hu C, Hui K, Jiang X. Non-immune functions of B7-H3: bridging tumor cells and the tumor vasculature. Front Oncol 2024; 14:1408051. [PMID: 38952550 PMCID: PMC11215132 DOI: 10.3389/fonc.2024.1408051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/04/2024] [Indexed: 07/03/2024] Open
Abstract
B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in various types of cancer and their tumor vasculature, demonstrating significant associations with adverse clinical outcomes. In addition to its well-known immune functions, B7-H3 exhibits dual co-stimulatory/co-inhibitory roles in normal physiology and the tumor microenvironment. The non-immune functions of B7-H3 in tumor cells and the tumor vasculature, including promoting tumor cell anti-apoptosis, proliferation, invasion, migration, drug resistance, radioresistance, as well as affecting cellular metabolism and angiogenesis, have increasingly gained attention from researchers. Particularly, the co-expression of B7-H3 in both tumor cells and tumor endothelial cells highlights the higher potential and clinical utility of therapeutic strategies targeting B7-H3. This review aims to summarize the recent advances in understanding the non-immune functions of B7-H3 in tumors and provide insights into therapeutic approaches targeting B7-H3, focusing on its co-expression in tumor cells and endothelial cells. The aim is to establish a theoretical foundation and practical reference for the development and optimization of B7-H3-targeted therapies.
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Affiliation(s)
- Shuo Wu
- Department of Oncology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
| | - Chenxi Hu
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
| | - Kaiyuan Hui
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
| | - Xiaodong Jiang
- Department of Oncology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
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16
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Yeo SP, Kua L, Tan JW, Lim JK, Wong FHS, Santos MD, Poh CM, Goh AXH, Koh XY, Zhou X, Rajarethinam R, Chen Q, Her Z, Horak ID, Low L, Tan KW. B7-H3-Targeting Chimeric Antigen Receptors Epstein-Barr Virus-specific T Cells Provides a Tumor Agnostic Off-The-Shelf Therapy Against B7-H3-positive Solid Tumors. CANCER RESEARCH COMMUNICATIONS 2024; 4:1410-1429. [PMID: 38717140 PMCID: PMC11149603 DOI: 10.1158/2767-9764.crc-23-0538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/14/2024] [Accepted: 05/03/2024] [Indexed: 06/07/2024]
Abstract
Encouraged by the observations of significant B7-H3 protein overexpression in many human solid tumors compared to healthy tissues, we directed our focus towards targeting B7-H3 using chimeric antigen receptor (CAR) T cells. We utilized a nanobody as the B7-H3-targeting domain in our CAR construct to circumvent the stability issues associated with single-chain variable fragment-based domains. In efforts to expand patient access to CAR T-cell therapy, we engineered our nanobody-based CAR into human Epstein-Barr virus-specific T cells (EBVST), offering a readily available off-the-shelf treatment. B7H3.CAR-armored EBVSTs demonstrated potent in vitro and in vivo activities against multiple B7-H3-positive human tumor cell lines and patient-derived xenograft models. Murine T cells expressing a murine equivalent of our B7H3.CAR exhibited no life-threatening toxicities in immunocompetent mice bearing syngeneic tumors. Further in vitro evaluation revealed that while human T, B, and natural killer cells were unaffected by B7H3.CAR EBVSTs, monocytes were targeted because of upregulation of B7-H3. Such targeting of myeloid cells, which are key mediators of cytokine release syndrome (CRS), contributed to a low incidence of CRS in humanized mice after B7H3.CAR EBVST treatment. Notably, we showed that B7H3.CAR EBVSTs can target B7-H3-expressing myeloid-derived suppressor cells (MDSC), thereby mitigating MDSC-driven immune suppression. In summary, our data demonstrate that our nanobody-based B7H3.CAR EBVSTs are effective as an off-the-shelf therapy for B7-H3-positive solid tumors. These cells also offer an avenue to modulate the immunosuppressive tumor microenvironment, highlighting their promising clinical potential in targeting solid tumors. SIGNIFICANCE Clinical application of EBVSTs armored with B7-H3-targeting CARs offer an attractive solution to translate off-the-shelf CAR T cells as therapy for solid tumors.
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Affiliation(s)
| | - Lindsay Kua
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
| | - Jin Wei Tan
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
| | | | - Fiona HS Wong
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
| | | | | | - Angeline XH Goh
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
| | | | | | - Ravisankar Rajarethinam
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Zhisheng Her
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Ivan D. Horak
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
| | - Lionel Low
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
| | - Kar Wai Tan
- Tessa Therapeutics Ltd, Singapore
- Tikva Allocell Pte Ltd, Singapore
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17
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Gao J, Tan W, Yuan L, Wang H, Wen J, Sun K, Chen X, Wang S, Deng W. Antitumour mechanisms of traditional Chinese medicine elicited by regulating tumour-associated macrophages in solid tumour microenvironments. Heliyon 2024; 10:e27220. [PMID: 38463777 PMCID: PMC10923716 DOI: 10.1016/j.heliyon.2024.e27220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 02/06/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Tumour-associated macrophages (TAMs), particularly M2-TAMs, constitute the largest proportion of immune cells in the solid tumour microenvironment, playing a crucial role in tumour progression and correlating with poor prognosis. TAMs promote the proliferation, invasion, and metastasis of tumour cells by remodelling the extracellular matrix, inhibiting immunity, promoting immune escape and tumour angiogenesis, and affecting cell metabolism. Traditional Chinese medicine (TCM) has been used clinically in China for millennia. Chinese herbs exhibit potent antitumour effects with minimal to no toxicity, substantially contributing to prolonging the lives of patients with cancer and improving their quality of life. TCM has unique advantages in improving the solid tumour microenvironment, particularly in regulating TAMs to further inhibit tumour angiogenesis, reduce drug resistance, reverse immunosuppression, and enhance antitumour immunity. This review highlights the TAM-associated mechanisms within the solid tumour microenvironment, outlines the recent advancements in TCM targeting TAMs for antitumour effects, emphasises the superiority of combining TCM with standard treatments or new nano-drug delivery systems, and evaluates the safety and efficacy of TCM combined with conventional treatments via clinical trials to provide insights and strategies for future research and clinical treatment.
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Affiliation(s)
- Jiamin Gao
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Weishan Tan
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Luyun Yuan
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Haoyue Wang
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Junkai Wen
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Kexiang Sun
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Xin Chen
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Shuyun Wang
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
| | - Wanli Deng
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200135, China
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18
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Zhang D, Huang H, Gao X, Yu G, Zhang X, Jin H, Xu R, Wang Z, Zhang G. High expression of B7-H3 on monocyte/macrophages in tumor microenvironment promotes lung cancer progression by inhibiting apoptosis. Transl Oncol 2024; 41:101874. [PMID: 38262113 PMCID: PMC10832491 DOI: 10.1016/j.tranon.2023.101874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/03/2023] [Accepted: 12/22/2023] [Indexed: 01/25/2024] Open
Abstract
Monocyte/macrophages constitute a significant population of tumor-infiltrating immune cells and play a crucial role in tumor growth, invasion, and metastasis. B7-H3, has immune regulatory functions, however, it is unclear whether B7-H3 expressed on monocyte/macrophages plays a significance role in tumor progression. We found B7-H3 was high-expressed on monocyte/macrophages in tumor microenvironment compared with adjacent tissues in lung cancer, and its expression level was positively correlated with the number of monocyte/macrophages. Furthermore, the expression of B7-H3 was related to clinical stage and lymph node metastasis. Moreover, miR-29a-3p negatively regulated B7-H3, and the expression of B7-H3 on THP-1-derived macrophages was regulated by secreting exosomes containing miR-29a-3p. In addition, knockdown of B7-H3 promoted macrophage apoptosis under hypoxia. Mechanistically, B7-H3 enhanced the antiapoptotic ability of macrophage by up-regulating HIF-1ɑ via activating NF-κB. Taken together, these results imply that B7-H3 as a therapeutic target could hold promise for enhancing anti-tumor immune responses in individuals diagnosed with lung cancer.
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Affiliation(s)
- Dongze Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Haitao Huang
- Department of Thoracic surgery, The First Affiliated Hospital of Soochow University, China
| | - Xin Gao
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, China
| | - Gehua Yu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Haiyan Jin
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Ruyan Xu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Zhenxin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, China.
| | - Guangbo Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China.
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19
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Jiang Y, Liu J, Chen L, Qian Z, Zhang Y. A promising target for breast cancer: B7-H3. BMC Cancer 2024; 24:182. [PMID: 38326735 PMCID: PMC10848367 DOI: 10.1186/s12885-024-11933-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/29/2024] [Indexed: 02/09/2024] Open
Abstract
Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.
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Affiliation(s)
- Ying Jiang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Jiayu Liu
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China
| | - Zhiwen Qian
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China
| | - Yan Zhang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China.
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China.
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20
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Mei J, Cai Y, Zhu H, Jiang Y, Fu Z, Xu J, Chen L, Yang K, Zhao J, Song C, Zhang Y, Mao W, Yin Y. High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors in triple-negative breast cancer. NPJ Breast Cancer 2024; 10:11. [PMID: 38280882 PMCID: PMC10821876 DOI: 10.1038/s41523-024-00618-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 01/06/2024] [Indexed: 01/29/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.
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Affiliation(s)
- Jie Mei
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
- The First Clinical Medicine College, Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yun Cai
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China
| | - Hongjun Zhu
- Department of Oncology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, 226006, China
| | - Ying Jiang
- Department of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, 214023, China
| | - Ziyi Fu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
| | - Junying Xu
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China
| | - Kai Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
- The First Clinical Medicine College, Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Jinlu Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Chenghu Song
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yan Zhang
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China.
- Department of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, 214023, China.
| | - Wenjun Mao
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China.
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
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Du W, Xia X, Hu F, Yu J. Extracellular matrix remodeling in the tumor immunity. Front Immunol 2024; 14:1340634. [PMID: 38332915 PMCID: PMC10850336 DOI: 10.3389/fimmu.2023.1340634] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 12/28/2023] [Indexed: 02/10/2024] Open
Abstract
The extracellular matrix (ECM) is a significant constituent of tumors, fulfilling various essential functions such as providing mechanical support, influencing the microenvironment, and serving as a reservoir for signaling molecules. The abundance and degree of cross-linking of ECM components are critical determinants of tissue stiffness. In the process of tumorigenesis, the interaction between ECM and immune cells within the tumor microenvironment (TME) frequently leads to ECM stiffness, thereby disrupting normal mechanotransduction and promoting malignant progression. Therefore, acquiring a thorough comprehension of the dysregulation of ECM within the TME would significantly aid in the identification of potential therapeutic targets for cancer treatment. In this regard, we have compiled a comprehensive summary encompassing the following aspects: (1) the principal components of ECM and their roles in malignant conditions; (2) the intricate interaction between ECM and immune cells within the TME; and (3) the pivotal regulators governing the onco-immune response in ECM.
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Affiliation(s)
- Wei Du
- Department of Targeting Therapy and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Xueming Xia
- Division of Head & Neck Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fan Hu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jiayun Yu
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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22
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Koumprentziotis IA, Theocharopoulos C, Foteinou D, Angeli E, Anastasopoulou A, Gogas H, Ziogas DC. New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3. Vaccines (Basel) 2024; 12:54. [PMID: 38250867 PMCID: PMC10820813 DOI: 10.3390/vaccines12010054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.
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Chen S, Zhan S, Ding S, Zhang Q, Xuan H, Zhang X, Cao L. B7-H3 and CD47 co-expression in gastric cancer is a predictor of poor prognosis and potential targets for future dual-targeting immunotherapy. J Cancer Res Clin Oncol 2023; 149:16609-16621. [PMID: 37715830 DOI: 10.1007/s00432-023-05408-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/05/2023] [Indexed: 09/18/2023]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most prevalent types of cancer worldwide. B7-H3, an immune checkpoint molecule with promising potential, has been found to be overexpressed in various cancers. CD47 is an anti-phagocytic molecule that interacts with the signal regulatory protein alpha (SIRPα) to affect phagocytes. The relationship between the expression of B7-H3 and CD47, two potential therapeutic targets found in tumor cells, remains unknown. In this study, our objective is to investigate the clinical significance of co-expression of B7-H3 and CD47, as well as the potential therapeutic value of combination therapy in GC. METHODS We utilized immunohistochemistry (IHC) to assess the expression of B7-H3, CD47, CD68, CD86 and CD163 in tissue microarrays obtained from 268 GC patients who underwent surgeries. Western blotting was employed to assess the protein level of B7-H3 and CD47 in GC tissues. The co-localization of B7-H3/CD47 and CD68 in GC tissues was determined using multiplex immunohistochemistry (m-IHC). We further verified the relationship between B7-H3/CD47 and macrophage infiltration via flow cytometry. To estimate the clinical outcomes of patients from different subgroups, we employed the Kaplan-Meier curve and the Cox model. RESULTS Among the 268 GC cases, a total of 180 cases exhibited positive expression of B7-H3, while 122 cases showed positive expression of CD47. In fresh GC clinical tissues, B7-H3 and CD47 protein level was also higher in tumor tissue than in adjacent normal tissue. Remarkably, 91 cases demonstrated co-expression of B7-H3 and CD47. We observed a significant correlation between B7-H3 expression and tumor stage (P = 0.001), differentiation (P = 0.045), and depth (P = 0.003). Additionally, there was a significant association between B7-H3 and CD47 expression (P = 0.018). The percentage of B7-H3 and CD47 double positive cells in fresh GC tumor tissues were elevated compared with control adjacent tissues regardless of CD45- or CD45+ cells (P = 0.0029, P = 0.0012). Patients with high B7-H3 or CD47 expression had significantly lower overall survival (OS) rates compared to those with low expression levels (P = 0.0176 or P = 0.0042). Surprisingly, patients with combined high expression of B7-H3 and CD47 exhibited a considerably worse prognosis than others (P = 0.0007). Univariate analysis revealed that cases with high expression of B7-H3, CD47, or both had significantly higher hazard ratios (HR) than cases with low expression of these markers. Furthermore, the results of multivariate analysis indicated that B7-H3/CD47 co-expression and CD47 expression alone are independent prognostic factors for overall survival. Moreover, significant correlations were observed between B7-H3 and CD68 expression, CD47 and CD68 expression, as well as B7-H3/CD47 co-expression and CD68 expression in GC patients (P < 0.001, P = 0.003, and P < 0.001). Flow cytometry test showed that the percentage of CD68-positive cells but not CD86-positive cells among B7-H3-positive or CD47-positive immune cells in GC tumor tissue was elevated significantly compared with adjacent tissue. CONCLUSION Our findings demonstrated a correlation between B7-H3 expression and CD47 expression in GC patient tissues. Co-expression of B7-H3 and CD47 can serve as an indicator of poor prognosis in GC patients. In GC tumor tissue, but not adjacent tissue, B7-H3 and CD47 expression was accompanied with macrophage infiltration.
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Affiliation(s)
- Siji Chen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
| | - Shenghua Zhan
- Department of Pathology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Sisi Ding
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
| | - Qiange Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
| | - Hanqin Xuan
- Department of Pathology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 178 Ganjiang East Road, Suzhou, 215006, China.
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Zhang X, Guo H, Chen J, Xu C, Wang L, Ke Y, Gao Y, Zhang B, Zhu J. Highly proliferative and hypodifferentiated CAR-T cells targeting B7-H3 enhance antitumor activity against ovarian and triple-negative breast cancers. Cancer Lett 2023; 572:216355. [PMID: 37597651 DOI: 10.1016/j.canlet.2023.216355] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 08/21/2023]
Abstract
Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting B7-H3 and incorporating a 4-1BB costimulatory molecule with STAT3-and STAT5-related activation motifs was constructed using lentivirus transduction. B7-H3, a tumor-associated antigen, and its scFv antibody endowed CAR-T cells with tumor-specific targeting capabilities. Moreover, the integration of the trIL2RB and YRHQ motifs stimulated STAT5 and STAT3 in an antigen-dependent manner, inducing a remarkable increase in the proliferation and survival of CAR-T cells via the activation of the JAK-STAT signaling pathway. Besides, the proportion of less-differentiated T cells increased among BB-trIL2RB-z(YRHQ) CAR-T cells. Moreover, BB-trIL2RB-z(YRHQ) effectively inhibited ovarian cancer (OC) and triple-negative breast cancer (TNBC) in vivo at low doses, without high serum levels of inflammatory cytokines and organ toxicity. Therefore, our study proposes a combination of elements for the construction of superior pluripotent CAR-T cells to provide an effective strategy for the treatment of intractable solid tumors.
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Affiliation(s)
- Xiaoshuai Zhang
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Haiyan Guo
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jie Chen
- Jecho Biopharmaceutical Institute, Shanghai, 200240, China
| | - Chenxiao Xu
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Lei Wang
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yong Ke
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yang Gao
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Baohong Zhang
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Jianwei Zhu
- Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China; Jecho Biopharmaceutical Institute, Shanghai, 200240, China
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25
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Fan X, Huang J, Hu B, Zhou J, Chen L. Tumor-expressed B7-H3 promotes vasculogenic mimicry formation rather than angiogenesis in non-small cell lung cancer. J Cancer Res Clin Oncol 2023; 149:8729-8741. [PMID: 37129607 DOI: 10.1007/s00432-023-04790-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 04/15/2023] [Indexed: 05/03/2023]
Abstract
BACKGROUND Vasculogenic mimicry (VM), an alternative microvascular circulation independent of angiogenesis, is formed by aggressive cancer cells. Tumor-expressed B7-H3 has been reported to promote VM formation in hepatocellular carcinoma and modulate angiogenesis in breast cancer and colorectal cancer. However, its effects on VM generation and angiogenesis in non-small cell Lung cancer (NSCLC) remained to be elucidated. METHODS CRISPR/Cas9-mediated B7-H3 knockout (KO) was conducted in NSCLC A549 and H3255 cells. The expression of VM-related proteins, including vascular endothelial (VE)-cadherin and matrix metalloproteinase 14 (MMP14), and the secretion of vascular endothelial growth factor (VEGF) were measured by western blotting and chemiluminescence assay in both B7-H3 KO and mock-edited A549 and H3255 cells. To examine VM formation, a three-dimensional (3D) culture model was used for B7-H3 KO and mock A549 and H3255 cells. For in vivo analysis, xenograft mice models were established using B7-H3 KO and mock-edited A549 cells, and immunohistochemical (CD31) and histochemical (periodic acid-Schiff, PAS) double staining were performed to identify VM and endothelial vessels in tumor tissues. Finally, specific signaling inhibitors were used to analyze B7-H3-induced signaling pathway responsible for VE-cadherin and MMP14 expression and VM generation. RESULTS Higher expression of B7-H3 was associated with a worse prognosis and more advanced T-category in NSCLC. CRISPR/Cas9-mediated B7-H3 KO in A549 and H3255 cells led to decreased expression of VE-cadherin and MMP14; however, the secretion of VEGF by the two cell lines remained unchanged. In the 3D cell culture model, both B7-H3 KO A549 and H3255 cells showed a significant reduction in the formation of capillary-like tubular structures compared to mock-edited cells. In the in vivo xenograft model, mock-edited A549 cells formed excessive PAS+ CD31- VM channels, while B7-H3 KO restrained VM formation in the xenograft tumors. However, no significant differences were found in CD31+ endothelial vessels between xenografts formed by B7-H3 KO and mock-edited A549 cells. Finally, we analyzed the signaling pathway responsible for B7-H3-induced VM formation and found that selective inhibition of the phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT) hyperactivation by LY294002 was associated with decreased expression of MMP14 and VE-cadherin, and in vitro VM formation by both A549 and H3255 cells. CONCLUSIONS Tumor-expressed B7-H3 acts via PI3K/AKT signaling pathway to promote VM formation by NSCLC cells while bears no effects on angiogenesis in NSCLC.
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Affiliation(s)
- Xingyu Fan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Junfeng Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bingqi Hu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Zhou
- Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Liwen Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
- Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
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Huang X, Guo J, Wang S, Lin Z, Zhao S, Li W, Wang Y, Zhu C, Lv J, Qiu W. Global research trends on B7-H3 for cancer immunotherapy: A bibliometric analysis (2012-2022). Hum Vaccin Immunother 2023; 19:2246498. [PMID: 37635349 PMCID: PMC10464541 DOI: 10.1080/21645515.2023.2246498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/13/2023] [Accepted: 08/05/2023] [Indexed: 08/29/2023] Open
Abstract
Immunotherapy has revolutionized cancer treatment. B7-H3 is a promising target for cancer immunotherapy (CI). The present study aimed to utilize bibliometric methods to assess the current research status and explore future trends in the use of B7-H3 for CI. We collected publications related to B7-H3/CI from the Clarivate Web of Science Core Collection database. VOSviewer, Microsoft Excel, the bibliometrix R package, and an online platform were used to conduct qualitative and visualized analyses of the literature. A total of 555 papers were analyzed, revealing a significant increase in annual publications since 2018. The most productive countries were China and the USA, and the leading institutions were Soochow University and Sichuan University. Zang and Ferrone were the most popular authors. Among the journals, Frontiers in Immunology had the highest number of papers, whereas Clinical Cancer Research was the most influential. Historical citation analysis reveals the development of B7-H3/CI. Top-cited papers and keyword analyses were performed to highlight current hotspots in the domain. Using cluster analysis, we classified all keywords into four clusters: "immunotherapy," "co-stimulatory molecule," "B7 family," and "PD-L1." Finally, Trends analysis suggested that future research might focus on "chimeric antigen receptor," "pathways," and "targeting B7-H3." This is the first bibliometric crosstalk analysis between B7-H3 and CI. Our study illustrates that the topic of B7-H3/CI is very popular and has great clinical implications and that the number of correlative publications will continue to increase. B7-H3-based CI may lead to new research trends.
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Affiliation(s)
- Xiaojuan Huang
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Guo
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shasha Wang
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhongkun Lin
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shufen Zhao
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenqian Li
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yan Wang
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chunyang Zhu
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Lv
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wensheng Qiu
- Department of Oncology, Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
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27
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Mortezaee K. B7-H3 immunoregulatory roles in cancer. Biomed Pharmacother 2023; 163:114890. [PMID: 37196544 DOI: 10.1016/j.biopha.2023.114890] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/06/2023] [Accepted: 05/12/2023] [Indexed: 05/19/2023] Open
Abstract
B7 homolog 3 (B7-H3, also called CD276) is a checkpoint of B7 family that is aberrantly and consistently expressed in several human cancers, and its overexpression correlates with weak prognosis. B7-H3 is expressed on a number of cells, and it acts as a driver of immune evasion. This is mediated through hampering T cell infiltration and promoting exhaustion of CD8+ T cells. Increased B7-H3 activity also promotes macrophage polarity toward pro-tumor type 2 (M2) phenotype. In addition, high B7-H3 activity induces aberrant angiogenesis to promote hypoxia, a result of which is resistance to common immune checkpoint inhibitor (ICI) therapy. This is mediated through the impact of hypoxia on dampening CD8+ T cell recruitment into tumor area. The immunosuppressive property of B7-H3 offers insights into targeting this checkpoint as a desired approach in cancer immunotherapy. B7-H3 can be a target in blocking monoclonal antibodies (mAbs), combination therapies, chimeric antigen receptor-modified T (CAR-T) cells and bispecific antibodies.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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28
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Yuan Z, Li Y, Zhang S, Wang X, Dou H, Yu X, Zhang Z, Yang S, Xiao M. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer 2023; 22:48. [PMID: 36906534 PMCID: PMC10007858 DOI: 10.1186/s12943-023-01744-8] [Citation(s) in RCA: 323] [Impact Index Per Article: 161.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 02/11/2023] [Indexed: 03/13/2023] Open
Abstract
The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation and distant metastasis. Anticancer treatments including adjuvant therapies and targeted therapies are effective in eliminating cancer cells but in a limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role in tumor development through changes in macromolecule components, degradation enzymes and stiffness. These variations are under the control of cellular components in tumor tissue via the aberrant activation of signaling pathways, the interaction of the ECM components to multiple surface receptors, and mechanical impact. Additionally, the ECM shaped by cancer regulates immune cells which results in an immune suppressive microenvironment and hinders the efficacy of immunotherapies. Thus, the ECM acts as a barrier to protect cancer from treatments and supports tumor progression. Nevertheless, the profound regulatory network of the ECM remodeling hampers the design of individualized antitumor treatment. Here, we elaborate on the composition of the malignant ECM, and discuss the specific mechanisms of the ECM remodeling. Precisely, we highlight the impact of the ECM remodeling on tumor development, including proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, and immune escape. Finally, we emphasize ECM "normalization" as a potential strategy for anti-malignant treatment.
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Affiliation(s)
- Zhennan Yuan
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yingpu Li
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Sifan Zhang
- Department of Neurobiology, Harbin Medical University, Harbin, 150081, China
| | - Xueying Wang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - He Dou
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xi Yu
- Department of Gynecological Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Zhiren Zhang
- NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorder and Cancer Related Cardiovascular Diseases, Harbin, 150001, China
| | - Shanshan Yang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, 150000, China.
| | - Min Xiao
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer 2023; 22:43. [PMID: 36859240 PMCID: PMC9979440 DOI: 10.1186/s12943-023-01751-9] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
B7-H3 (CD276), a member of the B7 family of proteins, is a key player in cancer progression. This immune checkpoint molecule is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance. Furthermore, its drastic difference in protein expression levels between normal and tumor tissues suggests that targeting B7-H3 with drugs would lead to cancer-specific toxicity, minimizing harm to healthy cells. These properties make B7-H3 a promising target for cancer therapy.Recently, important advances in B7-H3 research and drug development have been reported, and these new findings, including its involvement in cellular metabolic reprograming, cancer stem cell enrichment, senescence and obesity, have expanded our knowledge and understanding of this molecule, which is important in guiding future strategies for targeting B7-H3. In this review, we briefly discuss the biology and function of B7-H3 in cancer development. We emphasize more on the latest findings and their underlying mechanisms to reflect the new advances in B7-H3 research. In addition, we discuss the new improvements of B-H3 inhibitors in cancer drug development.
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Affiliation(s)
- Ayechew Adera Getu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Abiye Tigabu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ming Zhou
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jianrong Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, USA
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Ming Tan
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
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Kazakova A, Sudarskikh T, Kovalev O, Kzhyshkowska J, Larionova I. Interaction of tumor‑associated macrophages with stromal and immune components in solid tumors: Research progress (Review). Int J Oncol 2023; 62:32. [PMID: 36660926 PMCID: PMC9851132 DOI: 10.3892/ijo.2023.5480] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/07/2022] [Indexed: 01/18/2023] Open
Abstract
Tumor‑associated macrophages (TAMs) are crucial cells of the tumor microenvironment (TME), which belong to the innate immune system and regulate primary tumor growth, immunosuppression, angiogenesis, extracellular matrix remodeling and metastasis. The review discusses current knowledge of essential cell‑cell interactions of TAMs within the TME of solid tumors. It summarizes the mechanisms of stromal cell (including cancer‑associated fibroblasts and endothelial cells)‑mediated monocyte recruitment and regulation of differentiation, as well as pro‑tumor and antitumor polarization of TAMs. Additionally, it focuses on the perivascular TAM subpopulations that regulate angiogenesis and lymphangiogenesis. It describes the possible mechanisms of reciprocal interactions of TAMs with other immune cells responsible for immunosuppression. Finally, it highlights the perspectives for novel therapeutic approaches to use combined cellular targets that include TAMs and other stromal and immune cells in the TME. The collected data demonstrated the importance of understanding cell‑cell interactions in the TME to prevent distant metastasis and reduce the risk of tumor recurrence.
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Affiliation(s)
- Anna Kazakova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
| | - Tatiana Sudarskikh
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
| | - Oleg Kovalev
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634009, Russian Federation
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk 634050, Russian Federation
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634009, Russian Federation
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31
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Tumor-promoting aftermath post-chemotherapy: A focus on breast cancer. Life Sci 2022; 310:121125. [DOI: 10.1016/j.lfs.2022.121125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/14/2022] [Accepted: 10/22/2022] [Indexed: 11/09/2022]
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Zhao B, Li H, Xia Y, Wang Y, Wang Y, Shi Y, Xing H, Qu T, Wang Y, Ma W. Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy. J Hematol Oncol 2022; 15:153. [PMID: 36284349 PMCID: PMC9597993 DOI: 10.1186/s13045-022-01364-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/30/2022] [Indexed: 11/28/2022] Open
Abstract
Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.
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Affiliation(s)
- Binghao Zhao
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Huanzhang Li
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Xia
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yaning Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yuekun Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yixin Shi
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Hao Xing
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Tian Qu
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Wenbin Ma
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
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Zhang H, Zhu S, Deng W, Li R, Zhou H, Xiong H. The landscape of chimeric antigen receptor T cell therapy in breast cancer: Perspectives and outlook. Front Immunol 2022; 13:887471. [PMID: 35935930 PMCID: PMC9354605 DOI: 10.3389/fimmu.2022.887471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 07/01/2022] [Indexed: 11/25/2022] Open
Abstract
Chimeric antigen receptor-T (CAR-T) cell therapy is a revolutionary adoptive cell therapy, which could modify and redirect T cells to specific tumor cells. Since CAR-T cell therapy was first approved for B cell-derived malignancies in 2017, it has yielded unprecedented progress in hematological tumors and has dramatically reshaped the landscape of cancer therapy in recent years. Currently, cumulative evidence has demonstrated that CAR-T cell therapy could be a viable therapeutic strategy for solid cancers. However, owing to the immunosuppressive tumor microenvironment (TME) and heterogenous tumor antigens, the application of CAR-T cell therapy against solid cancers requires circumventing more challenging obstacles. Breast cancer is characterized by a high degree of invasiveness, malignancy, and poor prognosis. The review highlights the underlying targets of CAR-T cell therapy in breast cancer, summarizes the challenges associated with CAR-T cell therapy, and proposes the strategies to overcome these challenges, which provides a novel approach to breast cancer treatment.
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Zhou J, Wang L, Peng C, Peng F. Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology. Front Pharmacol 2022; 13:886198. [PMID: 35784750 PMCID: PMC9242535 DOI: 10.3389/fphar.2022.886198] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited.
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Affiliation(s)
- Jianbo Zhou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Li Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Fu Peng, ; Cheng Peng,
| | - Fu Peng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- *Correspondence: Fu Peng, ; Cheng Peng,
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Li Y, Ganesan K, Chen J. Role of Biological Mediators of Tumor-Associated Macrophages in Breast Cancer Progression. Curr Med Chem 2022; 29:5420-5440. [PMID: 35619312 DOI: 10.2174/0929867329666220520121711] [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: 10/14/2021] [Revised: 01/06/2022] [Accepted: 02/17/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Breast cancer (BRCA) has become the most common cancer worldwide. The tumor microenvironment (TME) in the breast exerts a crucial role in promoting BRCA initiation, progression, and metastasis. Tumor-associated macrophages (TAMs) are the primary component of tumor-infiltrating immune cells through biological mediators which convert TME into malignant tumors. Combinations of these biological mediators can promote tumor growth, metastasis, angiogenesis, immune suppression, and limit the anti-tumor activity of conventional chemotherapy and radiotherapy. OBJECTIVES The present study aimed to highlight the functions of several biological mediators in the breast which generate TME into malignant tumors. Furthermore, this review offers a rationale for TAM-targeted therapy as a novel treatment strategy for BRCA Results: this review emphasizes TAM-associated biological mediators of TME viz., cancer-associated fibroblasts, endothelial cells, adipocytes, tumor-derived exosomes, extracellular matrix, and other immune cells, which facilitates TME into malignant tumors. Evidence suggests that the increased infiltration of TAMs and elevated expression of TAM-related genes are associated with a poor prognosis of BRCA. Based on these findings, TAM-targeted therapeutic strategies, including inhibitors of CSF-1/CSF-1R, CCL2/CCR2, CCL5-CCR5, bisphosphonate, nanoparticle, and exosomal-targeted delivery have been developed, and are currently being employed in intervention trials. CONCLUSION This review concludes the roles of biological mediators of TME interact with TAMs in BRCA that provide a rationale for TAM-targeted therapy as a novel treatment approach for BRCA.
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Affiliation(s)
- Yan Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, China
| | - Kumar Ganesan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jianping Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
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Pretreatment of umbilical cord derived MSCs with IFN-γ and TNF-α enhances the tumor-suppressive effect on acute myeloid leukemia. Biochem Pharmacol 2022; 199:115007. [DOI: 10.1016/j.bcp.2022.115007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 01/27/2023]
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Wang S, Zhang X, Ning H, Dong S, Wang G, Sun R. B7 homolog 3 induces lung metastasis of breast cancer through Raf/MEK/ERK axis. Breast Cancer Res Treat 2022; 193:405-416. [PMID: 35312883 DOI: 10.1007/s10549-022-06520-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 01/05/2022] [Indexed: 12/22/2022]
Abstract
PURPOSE The essential action of B7 homolog 3 (B7-H3) in different diseases and cancers has been documented. We here focused on its role in breast cancer through the Raf/MEK/ERK axis regarding lung metastasis. METHODS Expression pattern of B7-H3 was determined in breast cancer tissues and cells with its correlation with prognosis analyzed. Then, through transfection of lentivirus vector expressing B7-H3-shRNA, overexpression vector of B7-H3 (B7-H3-LV), U0126 (small molecule inhibitor of MEK), or PD98059 (small molecule inhibitor of ERK), the in vitro and in vivo effects of B7-H3 in breast cancer cell biological processes, and lung metastasis were analyzed in relation to the Raf/MEK/ERK axis. RESULTS We discovered elevated B7-H3 in breast cancer and its elevation associated with poor prognosis. B7-H3 promoted the malignant properties of breast cancer cells, accompanied with increased N-cadherin and vimentin and reduced E-cadherin. Additionally, overexpression of B7-H3 accelerated the lung metastasis in breast cancer in vivo. All the above promoting action of B7-H3 was achieved through activation of the Raf/MEK/ERK signaling pathway. CONCLUSION Taken together, B7-H3 can promote lung metastasis in breast cancer through activation of the Raf/MEK/ERK axis.
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Affiliation(s)
- Shuai Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, No. 2428, Yuhe Road, Weifang, 261031, Shandong Province, China
| | - Xinyan Zhang
- Department of Intervention, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Weihai, 264200, China
| | - Houfa Ning
- School of Medical Imaging, Weifang Medical University, No. 7166, Baotong West Street, Weifang, 261053, Shandong Province, China
| | - Senyi Dong
- School of Medical Imaging, Weifang Medical University, No. 7166, Baotong West Street, Weifang, 261053, Shandong Province, China
| | - Guangzhi Wang
- School of Medical Imaging, Weifang Medical University, No. 7166, Baotong West Street, Weifang, 261053, Shandong Province, China.
| | - Ruimei Sun
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, No. 2428, Yuhe Road, Weifang, 261031, Shandong Province, China.
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Lin HJ, Liu Y, Lofland D, Lin J. Breast Cancer Tumor Microenvironment and Molecular Aberrations Hijack Tumoricidal Immunity. Cancers (Basel) 2022; 14:cancers14020285. [PMID: 35053449 PMCID: PMC8774102 DOI: 10.3390/cancers14020285] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Immune therapy is designed to stimulate tumoricidal effects in a variety of solid tumors including breast carcinomas. However, the emergence of resistant clones leads to treatment failure. Understanding the molecular, cellular, and microenvironmental aberrations is crucial to uncovering underlying mechanisms and developing advanced strategies for preventing or combating these resistant malignancies. This review will summarize research findings revealing various mechanisms employed to hijack innate and adaptive immune surveillance mechanisms, develop hypoxic and tumor promoting metabolism, and foster an immune tolerance microenvironment. In addition, it will highlight potential targets for therapeutic approaches. Abstract Breast cancer is the most common malignancy among females in western countries, where women have an overall lifetime risk of >10% for developing invasive breast carcinomas. It is not a single disease but is composed of distinct subtypes associated with different clinical outcomes and is highly heterogeneous in both the molecular and clinical aspects. Although tumor initiation is largely driven by acquired genetic alterations, recent data suggest microenvironment-mediated immune evasion may play an important role in neoplastic progression. Beyond surgical resection, radiation, and chemotherapy, additional therapeutic options include hormonal deactivation, targeted-signaling pathway treatment, DNA repair inhibition, and aberrant epigenetic reversion. Yet, the fatality rate of metastatic breast cancer remains unacceptably high, largely due to treatment resistance and metastases to brain, lung, or bone marrow where tumor bed penetration of therapeutic agents is limited. Recent studies indicate the development of immune-oncological therapy could potentially eradicate this devastating malignancy. Evidence suggests tumors express immunogenic neoantigens but the immunity towards these antigens is frequently muted. Established tumors exhibit immunological tolerance. This tolerance reflects a process of immune suppression elicited by the tumor, and it represents a critical obstacle towards successful antitumor immunotherapy. In general, immune evasive mechanisms adapted by breast cancer encompasses down-regulation of antigen presentations or recognition, lack of immune effector cells, obstruction of anti-tumor immune cell maturation, accumulation of immunosuppressive cells, production of inhibitory cytokines, chemokines or ligands/receptors, and up-regulation of immune checkpoint modulators. Together with altered metabolism and hypoxic conditions, they constitute a permissive tumor microenvironment. This article intends to discern representative incidents and to provide potential innovative therapeutic regimens to reinstate tumoricidal immunity.
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Affiliation(s)
- Huey-Jen Lin
- Department of Medical & Molecular Sciences, University of Delaware, Willard Hall Education Building, 16 West Main Street, Newark, DE 19716, USA
- Correspondence: ; Tel.: +1-302-831-7576; Fax: +1-302-831-4180
| | - Yingguang Liu
- Department of Molecular and Cellular Sciences, College of Osteopathic Medicine, Liberty University, 306 Liberty View Lane, Lynchburg, VA 24502, USA;
| | - Denene Lofland
- Department of Microbiology and Immunology, Tower Campus, Drexel University College of Medicine, 50 Innovation Way, Wyomissing, PA 19610, USA;
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, University of Maryland School of Medicine and Greenebaum Comprehensive Cancer Center, 108 N. Greene Street, Baltimore, MD 21201, USA;
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Feng R, Chen Y, Liu Y, Zhou Q, Zhang W. The role of B7-H3 in tumors and its potential in clinical application. Int Immunopharmacol 2021; 101:108153. [PMID: 34678689 DOI: 10.1016/j.intimp.2021.108153] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
B7-H3 (CD276 molecule) is an immune checkpoint from the B7 family of molecules that acts more as a co-inhibitory molecule to promote tumor progression. It is abnormally expressed on tumor cells and can be induced to express on antigen-presenting cells (APCs) including dendritic cells (DCs) and macrophages. In the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing T cell response, promoting the polarization of tumor-associated macrophages (TAMs) to M2, inhibiting the function of DCs, and promoting the migration and invasion of cancer-associated fibroblasts (CAFs). In addition, through non-immunological functions, B7-H3 promotes tumor cell proliferation, invasion, metastasis, resistance, angiogenesis, and metabolism, or in the form of exosomes to promote tumor progression. In this process, microRNAs can regulate the expression of B7-H3. B7-H3 may serve as a potential biomarker for tumor diagnosis and a marker of poor prognosis. Immunotherapy targeting B7-H3 and the combination of B7-H3 and other immune checkpoints have shown certain efficacy. In this review, we summarized the basic characteristics of B7-H3 and its mechanism to promote tumor progression by inducing immunosuppression and non-immunological functions, as well as the potential clinical applications of B7-H3 and immunotherapy based on B7-H3.
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Affiliation(s)
- Ranran Feng
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Liu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qing Zhou
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wenling Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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Llinàs-Arias P, Íñiguez-Muñoz S, McCann K, Voorwerk L, Orozco JIJ, Ensenyat-Mendez M, Sesé B, DiNome ML, Marzese DM. Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:4139. [PMID: 34439290 PMCID: PMC8394958 DOI: 10.3390/cancers13164139] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 12/24/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15-20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.
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Affiliation(s)
- Pere Llinàs-Arias
- Cancer Epigenetics Laboratory at the Cancer Cell Biology Group, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain; (P.L.-A.); (S.Í.-M.); (M.E.-M.); (B.S.)
| | - Sandra Íñiguez-Muñoz
- Cancer Epigenetics Laboratory at the Cancer Cell Biology Group, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain; (P.L.-A.); (S.Í.-M.); (M.E.-M.); (B.S.)
| | - Kelly McCann
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA;
| | - Leonie Voorwerk
- Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands;
| | - Javier I. J. Orozco
- Saint John’s Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA;
| | - Miquel Ensenyat-Mendez
- Cancer Epigenetics Laboratory at the Cancer Cell Biology Group, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain; (P.L.-A.); (S.Í.-M.); (M.E.-M.); (B.S.)
| | - Borja Sesé
- Cancer Epigenetics Laboratory at the Cancer Cell Biology Group, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain; (P.L.-A.); (S.Í.-M.); (M.E.-M.); (B.S.)
| | - Maggie L. DiNome
- Department of Surgery, David Geffen School of Medicine, University California Los Angeles (UCLA), Los Angeles, CA 90024, USA;
| | - Diego M. Marzese
- Cancer Epigenetics Laboratory at the Cancer Cell Biology Group, Institut d’Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain; (P.L.-A.); (S.Í.-M.); (M.E.-M.); (B.S.)
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CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1. Sci Rep 2021; 11:14849. [PMID: 34290311 PMCID: PMC8295264 DOI: 10.1038/s41598-021-94360-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.
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Targeting tumor-associated macrophages as an antitumor strategy. Biochem Pharmacol 2020; 183:114354. [PMID: 33279498 DOI: 10.1016/j.bcp.2020.114354] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022]
Abstract
Tumor-associated macrophages (TAMs) are the most widely infiltrating immune cells in the tumor microenvironment (TME). Clinically, the number of TAMs is closely correlated with poor outcomes in multiple cancers. The biological actions of TAMs are complex and diverse, including mediating angiogenesis, promoting tumor invasion and metastasis, and building an immunosuppressive microenvironment. Given these pivotal roles of TAMs in tumor development, TAM-based strategies are attractive and used in certain tumor therapies, including inhibition of angiogenic signalling, blockade of the immune checkpoint, and macrophage enhancement phagocytosis. Several attempts to develop TAM-targeted agents have been made to deplete TAMs or reprogram the behaviour of TAMs. Some have shown a favourable curative effect in monotherapy, combination with chemotherapy or immunotherapy in clinical trials. Additionally, a new macrophage-based cell therapeutic technology was recently developed by equipping macrophages with CAR molecules. It is expected to break through barriers to solid tumor treatment. Although TAM-related studies have yielded positive antitumor outcomes, further investigations are needed to better characterize TAMs, which will benefit further establishment of novel strategies for tumor therapy. Here, we concisely summarize the functions of TAMs in the TME and comprehensively introduce the latest TAM-based regimens in cancer treatment.
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