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      Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers

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          Abstract

          In recent years, breakthroughs have been made in tumor immunotherapy. However, tumor immunotherapy, particularly anti-PD-1/PD-L1 immune checkpoint inhibitors, is effective in only a small percentage of patients in solid cancer. How to improve the efficiency of cancer immunotherapy is an urgent problem to be solved. As we all know, the state of the tumor microenvironment (TME) is an essential factor affecting the effectiveness of tumor immunotherapy, and the cancer-associated fibroblasts (CAFs) in TME have attracted much attention in recent years. As one of the main components of TME, CAFs interact with cancer cells and immune cells by secreting cytokines and vesicles, participating in ECM remodeling, and finally affecting the immune response process. With the in-depth study of CAFs heterogeneity, new strategies are provided for finding targets of combination immunotherapy and predicting immune efficacy. In this review, we focus on the role of CAFs in the solid cancer immune microenvironment, and then further elaborate on the potential mechanisms and pathways of CAFs influencing anti-PD-1/PD-L1 immunotherapy. In addition, we summarize the potential clinical application value of CAFs-related targets and markers in solid cancers.

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          Most cited references133

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          TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

          Therapeutic antibodies that block the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer (mUC) 1–5 . However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here, we examined tumours from a large cohort of mUC patients treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). Lack of response was associated with a signature of transforming growth factor β (TGF-β) signalling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from the tumour parenchyma and instead found in the fibroblast- and collagen-rich peritumoural stroma—a common phenotype among patients with mUC. Using a mouse model that recapitulates this immune excluded phenotype, we found that therapeutic administration of a TGF-β blocking antibody together with anti–PD-L1 reduced TGF-β signalling in stromal cells, facilitated T cell penetration into the centre of the tumour, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding outcome in this setting and suggests that TGF-β shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T cell infiltration.
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            Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

            New England Journal of Medicine, 373(1), 23-34
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              Innate and adaptive immune cells in the tumor microenvironment.

              Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.
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                Author and article information

                Contributors
                metheuslp@163.com
                zlyyliuyang1440@zzu.edu.cn
                liulin@zzu.edu.cn
                fccgaosc@zzu.edu.cn
                zzugxy2022@163.com
                fengyudi00@163.com
                fccsunzq@zzu.edu.cn
                fcczhangy@zzu.edu.cn
                czw202112@zzu.edu.cn
                Journal
                Mol Cancer
                Mol Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                10 February 2023
                10 February 2023
                2023
                : 22
                : 29
                Affiliations
                [1 ]GRID grid.412633.1, ISNI 0000 0004 1799 0733, Department of Ultrasound, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China
                [2 ]GRID grid.412633.1, ISNI 0000 0004 1799 0733, Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China
                [3 ]GRID grid.414008.9, ISNI 0000 0004 1799 4638, Department of Radiotherapy, , Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, ; Zhengzhou, 450008 China
                [4 ]GRID grid.412633.1, ISNI 0000 0004 1799 0733, Department of Neurology, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China
                [5 ]GRID grid.412633.1, ISNI 0000 0004 1799 0733, Department of Colorectal Surgery, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China
                Article
                1731
                10.1186/s12943-023-01731-z
                9912573
                36759842
                1d0ad17d-60a8-4578-95eb-3fabb58ee4e4
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 13 November 2022
                : 24 January 2023
                Funding
                Funded by: The National Natural Science Foundation of China
                Award ID: 82173055, 81972663
                Funded by: The Youth Talent Innovation Team Support Program of Zhengzhou University
                Award ID: 32320290
                Funded by: The Provincial and Ministry co-constructed key projects of Henan medical science and technology
                Award ID: SBGJ202102134
                Funded by: Key scientific and technological research projects of Henan Provincial Department of Science and Technology
                Award ID: 212102310117
                Funded by: Henan Provincial Health Commission and Ministry of Health Co-construction Project, and Henan Provincial Health and Health Commission Joint Construction Project
                Award ID: LHGJ20200158
                Funded by: Henan Province young and middle-aged health science and technology innovation leading talent project
                Award ID: YXKC2022016
                Funded by: Henan Province Medical Affairs Technology Promotion Project
                Award ID: SYJS2022109
                Funded by: The Science Project of Henan Natural Science Foundation
                Award ID: 212300410074, 202300410446
                Categories
                Review
                Custom metadata
                © The Author(s) 2023

                Oncology & Radiotherapy
                cancer-associated fibroblasts,pd-1/pd-l1 inhibitors,immunotherapy
                Oncology & Radiotherapy
                cancer-associated fibroblasts, pd-1/pd-l1 inhibitors, immunotherapy

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