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      Heterogeneous Tumor-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient

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          Summary

          We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8 + and CD4 + T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8 + T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy.

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          Highlights

          • Differential progression of metastases during off-treatment period.

          • Coexistence of distinct tumor-immune microenvironments within the same individual.

          • Tumor regression and progression correlated with T cell infiltration and exclusion.

          • Clonal neoepitopes elicited reactivity of circulating CD8 + T cells.

          Abstract

          Distinct tumor immune microenvironments co-exist within a single individual and may help to explain the heterogeneous fates of metastatic lesions often observed post-therapy.

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          Most cited references37

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          Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.

          Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy. Copyright © 2015, American Association for the Advancement of Science.
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            Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

            Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
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              Immunological aspects of cancer chemotherapy.

              Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                24 August 2017
                24 August 2017
                : 170
                : 5
                : 927-938.e20
                Affiliations
                [1 ]Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
                [2 ]European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
                [3 ]Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [4 ]Ludwig Collaborative/Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [5 ]Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [6 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [7 ]Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [8 ]Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [9 ]Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [10 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [11 ]Department of Medicine, Weill Cornell Medical College, New York, NY, USA
                [12 ]Immunology and Microbial Pathogenesis Programs, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
                Author notes
                []Corresponding author snyderca@ 123456mskcc.org
                [∗∗ ]Corresponding author martin.miller@ 123456cruk.cam.ac.uk
                [13]

                Lead Contact

                Article
                S0092-8674(17)30832-2
                10.1016/j.cell.2017.07.025
                5589211
                28841418
                a6aed164-9470-41a2-a8ea-e7dddf1e5e25
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 January 2016
                : 6 June 2017
                : 14 July 2017
                Categories
                Article

                Cell biology
                Cell biology

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