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      Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy

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          Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.

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          Most cited references 139

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          Microenvironmental regulation of tumor progression and metastasis.

          Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
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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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              The biology and function of fibroblasts in cancer.

               Raghu Kalluri (2016)
              Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.

                Author and article information

                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                28 August 2019
                28 August 2019
                : 12
                [1 ]ISNI 0000 0004 1764 4566, GRID grid.452509.f, Department of Thoracic Surgery, , Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, ; Nanjing, China
                [2 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, The Fourth Clinical College of Nanjing Medical University, ; Nanjing, China
                [3 ]ISNI 0000 0004 1764 4566, GRID grid.452509.f, Department of Scientific Research, , Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, ; Nanjing, China
                [4 ]Jiangsu Biobank of Clinical Resources, Nanjing, 210009 China
                [5 ]ISNI 0000 0000 9776 7793, GRID grid.254147.1, Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, , China Pharmaceutical University, ; Nanjing, 210009 China
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                Funded by: FundRef http://dx.doi.org/10.13039/501100010909, Young Scientists Fund;
                Award ID: 81802277
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;
                Award ID: 2018M642198
                Award Recipient :
                Funded by: Jiangsu Provincial Medical Talent
                Award ID: ZDRCA2016033
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81872378
                Award Recipient :
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                © The Author(s) 2019


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