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      NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

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          Summary

          Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE 2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE 2 for immune evasion and that could be exploited for cancer therapy.

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          Highlights

          • NK cells recruit cDC1 into the tumor microenvironment

          • cDC1 recruitment depends on NK cell-derived chemokines CCL5 and XCL1

          • The NK cell/chemokine/cDC1 axis is associated with cancer patient survival

          • Tumor-derived PGE 2 impairs NK cell and cDC1 resulting in cancer immune evasion

          Abstract

          Natural killer cells recruit dendritic cells to the tumor microenvironment, and disruption of this process results in cancer immune evasion.

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          Most cited references 30

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          Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.

          Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8alpha+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8alpha+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8alpha+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
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            Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses

            To guide the design of immunotherapy strategies for patients with early stage lung tumors, we developed a multiscale immune profiling strategy to map the immune landscape of early lung adenocarcinoma lesions to search for tumor-driven immune changes. Utilizing a barcoding method that allows a simultaneous single cell analysis of the tumor, non-involved lung and blood cells together with multiplex tissue imaging to assess spatial cell distribution, we provide a detailed immune cell atlas of early lung tumors. We show that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments. Moreover, we identified changes in tumor infiltrating myeloid cell (TIM) subsets that likely compromise anti-tumor T cell immunity. Paired single cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies. Comparing single tumor cells with adjacent normal tissue and blood from patients with lung adenocarcinoma charts early changes in tumor immunity and provides insights to guide immunotherapy design.
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              Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.

              Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                22 February 2018
                22 February 2018
                : 172
                : 5
                : 1022-1037.e14
                Affiliations
                [1 ]Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
                [2 ]Cancer Inflammation and Immunity Group, CRUK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK
                [3 ]Bioinformatics, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
                [4 ]Tumour Cell Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
                Author notes
                []Corresponding author j.boettcher@ 123456tum.de
                [∗∗ ]Corresponding author caetano@ 123456crick.ac.uk
                [5]

                Present address: Institute of Molecular Immunology and Experimental Oncology, Klinikum München rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany

                [6]

                Lead Contact

                Article
                S0092-8674(18)30039-4
                10.1016/j.cell.2018.01.004
                5847168
                © 2018 Francis Crick Institute

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

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