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      The clinical role of the TME in solid cancer

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          Abstract

          The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)—in particular, the degree of tumour infiltration by cytotoxic T cells—can predict a patient’s clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.

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          Most cited references66

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          PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

          Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
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            Neutrophils in cancer: neutral no more.

            Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets.
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              Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

              Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.
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                Author and article information

                Contributors
                +410-955-3439 , ngirald1@jhmi.edu
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                9 November 2018
                8 January 2019
                : 120
                : 1
                : 45-53
                Affiliations
                [1 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Pathology Department, , The Johns Hopkins University School Of Medicine, ; Baltimore, MD USA
                [2 ]ISNI 0000 0001 0626 5681, GRID grid.418120.e, Urology Department, , Institut Mutualiste Montsouris, ; F-75014 Paris, France
                [3 ]GRID grid.414093.b, Oncology Department, , Hopital Européen Georges Pompidou, ; Paris, France
                [4 ]GRID grid.417925.c, INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team “Cancer, immune control and escape”, ; F-75006 Paris, France
                [5 ]GRID grid.417925.c, University Paris Descartes Paris 5, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, ; F-75006 Paris, France
                [6 ]GRID grid.417925.c, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, ; F-75006 Paris, France
                [7 ]ISNI 0000 0004 0387 2429, GRID grid.430276.4, Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), ; Singapore, Singapore
                [8 ]ISNI 0000 0001 2226 6748, GRID grid.452770.3, Programme Cartes d’Identité des Tumeurs, Ligue Nationale contre le Cancer, ; F-75013 Paris, France
                [9 ]ISNI 0000 0001 0626 5681, GRID grid.418120.e, Pathology Department, , Institut Mutualiste Montsouris, ; F-75014 Paris, France
                [10 ]ISNI 0000 0001 2188 0914, GRID grid.10992.33, University Paris Descartes Paris 5, Sorbonne Paris Cite, ; Paris, France
                Article
                327
                10.1038/s41416-018-0327-z
                6325164
                30413828
                6022668f-3c10-41a4-a281-0f67a43248d6
                © Cancer Research UK 2018

                Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

                History
                : 19 May 2018
                : 2 October 2018
                : 9 October 2018
                Categories
                Review Article
                Custom metadata
                © Cancer Research UK 2019

                Oncology & Radiotherapy
                cancer microenvironment,prognostic markers,immunosurveillance,cancer immunotherapy

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