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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe tumor microenvironment (TME) contains stromal cells and immune cells that shape cancer development and impact the response to tumor therapy (, ). Intratumoral immune cells comprise lymphocytes, such as T cells, B, cells and natural killer (NK) cells, and diverse populations of myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells (DCs) (, , ). The different myeloid cells within the TME fulfill distinct and sometimes opposing roles. Simplistically, intratumoral monocytes and M2-polarized macrophages can promote cancer cell growth, angiogenesis, and metastasis, as well as contribute to the establishment of an immunosuppressive environment. They are associated with tumor progression and poor clinical outcome (). In contrast, M1-polarized macrophages and DCs contribute to anti-tumor immunity and are associated with a favorable outcome ().The contribution of conventional DCs (cDCs) to anti-tumor immunity reflects their ability to present tumor antigens and to secrete cytokines that regulate T cell survival and effector function. cDCs can be divided into at least two subsets, conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells (cDC2) (, ). The cDC1 subset depends for its development on the transcription factor Batf3 and can be identified by the selective expression of the C-type lectin receptor DNGR-1 (aka CLEC9A) and the chemokine receptor XCR1 and, in non-lymphoid organs and in tumors, additional expression of the integrin αE (CD103) in the presence of low expression of CD11b. cDC1 are especially adept at taking up dead tumor cells and transporting tumor antigens to tumor-draining lymph nodes where they constitute the key DC subtype responsible for cross-priming anti-tumor CD8⁺ T cells (, ). In addition to this trafficking role, cDC1 also play a key role within tumors themselves. Intratumoral cDC1 attract T cells (), re-stimulate and expand tumor-specific CD8⁺ T cells (), and support T cell effector function by secreting interleukin (IL)-12 (). The overall importance of cDC1 in anti-tumor immunity is underscored by multiple studies demonstrating that the lack of cDC1 in Batf3^−/− mice abolishes the rejection of immunogenic tumors and the response to adoptive T cell therapy and to immune checkpoint blockade (, href="#bib23" rid="bib23" class=" bibr popnode">Hildner et al., 2008, href="#bib41" rid="bib41" class=" bibr popnode">Salmon et al., 2016, href="#bib42" rid="bib42" class=" bibr popnode">Sánchez-Paulete et al., 2016, href="#bib46" rid="bib46" class=" bibr popnode">Spranger et al., 2015).Human cDC1 are very rare within the TME and often excluded from early tumor stages, which might hinder anti-tumor immunity and contribute to cancer progression. Although intratumoral cDC1 have not been investigated in humans in as much detail as in mice, cDC1 abundance in human melanoma correlates with T cell infiltration and the ratio of cDC1-selective transcripts over macrophage-restricted transcripts can be used as a prognostic marker for cancer patient survival (href="#bib4" rid="bib4" class=" bibr popnode">Broz et al., 2014, href="#bib47" rid="bib47" class=" bibr popnode">Spranger et al., 2017). Therapies aimed at increasing cDC1 abundance in tumors or facilitating their activation may therefore boost anti-tumor immunity and potentially increase the responsiveness of cancer patients to immunotherapy (href="#bib4" rid="bib4" class=" bibr popnode">Broz et al., 2014, href="#bib41" rid="bib41" class=" bibr popnode">Salmon et al., 2016, href="#bib47" rid="bib47" class=" bibr popnode">Spranger et al., 2017). However, the mechanisms determining the abundance of cDC1 at the tumor site remain enigmatic and it is unclear whether cDC1 are actively recruited into the TME and if this requires the participation of other cell types.Prostaglandin E2 (PGE2) is a prostanoid with immune-regulatory function that is produced by many cell types and can further be released upon cell death (href="#bib19" rid="bib19" class=" bibr popnode">Hangai et al., 2016). We previously found that many tumors secrete PGE2 to suppress anti-cancer immunity (href="#bib54" rid="bib54" class=" bibr popnode">Zelenay et al., 2015). In such tumors, genetic ablation of cyclooxygenases, encoded by the Ptgs1 and Ptgs2 genes, leads to inability to produce PGE2 and renders the cancers susceptible to cDC1-dependent CD8⁺ T cell-mediated immune control (href="#bib54" rid="bib54" class=" bibr popnode">Zelenay et al., 2015). Mouse tumors lacking PGE2 production are therefore an ideal system in which to dissect the mechanisms underlying cDC1 accumulation. Here, we show that such tumors are infiltrated by cDC1, and we identify a key role for intratumoral NK cells in producing CCL5 and XCL1 chemokines that promote cDC1 recruitment. We provide evidence that a similar NK cell/chemokine functional axis determines cDC1 abundance in human melanoma, breast cancer, lung cancer, and head and neck squamous cell carcinoma and show that it impacts on patient survival. Finally, we uncover a role for PGE2 both in diminishing NK cell survival and function and in downregulating cDC1 responsiveness to chemoattractants. These data provide insights into the control of cDC1 accumulation in tumors in mice and humans and support the rational design of therapies aiming to increase cDC1 numbers in tumors that might help overcoming resistance to current immunotherapies.