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      Role of cancer‐associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer

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          Abstract

          The tumor microenvironment (TME) has been identified as one of the driving factors of tumor progression and invasion. Within this microenvironment, cancer‐associated fibroblasts (CAF) have multiple tumor‐promoting functions and play key roles in drug resistance, through multiple mechanisms, including extracellular matrix (ECM) remodeling, production of growth factors, cytokines, and chemokines, and modulation of metabolism and angiogenesis. More recently, a growing body of evidence has shown that CAF also modulate immune cell activity and suppress anti‐tumor immune response. In this review, we describe the current knowledge on CAF heterogeneity in terms of identity and functions. Moreover, we analyze how distinct CAF subpopulations differentially interact with immune cells, with a particular focus on T lymphocytes. We address how specific CAF subsets contribute to cancer progression through induction of an immunosuppressive microenvironment. Finally, we highlight potential therapeutic strategies for targeting CAF subpopulations in cancer.

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          Most cited references163

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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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              A framework for advancing our understanding of cancer-associated fibroblasts

              Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
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                Author and article information

                Contributors
                fatima.mechta-grigoriou@curie.fr
                Journal
                Immunol Rev
                Immunol Rev
                10.1111/(ISSN)1600-065X
                IMR
                Immunological Reviews
                John Wiley and Sons Inc. (Hoboken )
                0105-2896
                1600-065X
                19 May 2021
                July 2021
                : 302
                : 1 ( doiID: 10.1111/imr.v302.1 )
                : 259-272
                Affiliations
                [ 1 ] Institut Curie Stress and Cancer Laboratory Equipe labelisée Ligue Nationale Contre le Cancer PSL Research University Paris France
                [ 2 ] U830, Inserm Paris France
                Author notes
                [*] [* ] Correspondence

                Fatima Mechta‐Grigoriou, Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d’Ulm, F‐75005 Paris, France.

                Email: fatima.mechta-grigoriou@ 123456curie.fr

                Author information
                https://orcid.org/0000-0002-3751-6989
                Article
                IMR12978
                10.1111/imr.12978
                8360036
                34013544
                b13938c7-ca7c-4e0d-9fa9-174ae0a9aebb
                © 2021 Institut Curie, Stress and Cancer lab. Immunological Reviews published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 26 April 2021
                : 28 February 2021
                : 27 April 2021
                Page count
                Figures: 3, Tables: 0, Pages: 14, Words: 10996
                Funding
                Funded by: SIRIC
                Award ID: INCa‐DGOS‐4654
                Funded by: Ligue Nationale Contre le Cancer , doi 10.13039/501100004099;
                Funded by: Association pour la Recherche sur le Cancer , doi 10.13039/100007391;
                Funded by: ICGex
                Award ID: ANR‐10‐EQPX‐03
                Funded by: Institut Curie , doi 10.13039/501100010463;
                Award ID: PIC3i CAFi
                Award ID: PIC TME/T‐MEGA
                Funded by: Association Ruban Rose
                Funded by: Institut National Du Cancer , doi 10.13039/501100006364;
                Award ID: CaLYS INCa‐11692
                Award ID: INCa‐DGOS‐Inserm‐12554
                Award ID: STROMAE INCa‐DGOS‐9963
                Funded by: Institut National de la Santé et de la Recherche Médicale , doi 10.13039/501100001677;
                Award ID: PC201317
                Funded by: Fondation Simone et Cino Del Duca , doi 10.13039/100009515;
                Funded by: Fondation Chercher et Trouver
                Categories
                Invited Review
                Invited Reviews
                Invited Review Themed Issue
                Custom metadata
                2.0
                July 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:12.08.2021

                cancer,cancer‐associated fibroblasts,heterogeneity,immunosuppression,immunotherapy,t lymphocytes

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