Abstract
Natural killer (NK) cells recruit conventional type 1 dendritic cells (cDC1) to the tumor microenvironment.
Major finding: Natural killer (NK) cells recruit conventional type 1 dendritic cells (cDC1) to the tumor microenvironment.
Concept: NK cells produce the chemokines CCL5 and XCL1 to recruit cDC1, which is blocked by tumor-derived PGE2.
Impact: Chemokines may represent therapeutic targets to enhance cDC1 recruitment and antitumor immunity.
Conventional type 1 dendritic cells (cDC1) promote antitumor immunity and are linked to response to immunotherapy. However, cDC1 are rarely found in the tumor microenvironment (TME) of human tumors, and the mechanisms that control their abundance are not understood. Strategies to increase cDC1 abundance might potentially enhance the antitumor immunity and suppress tumor progression. Prostaglandin E2 (PGE2) suppresses antitumor immunity and is secreted by many tumors, and Böttcher and colleagues found that cDC1 accumulate in the tumor microenvironment in BRAFV600E melanomas when the cyclooxygenases (COX) required for PGE2 production (Pgts1 and Pgts2) are deleted from tumor cells. This finding suggested that tumor-derived PGE2 may disrupt cDC1 accumulation. The accumulation of cDC1 in the tumor microenvironment required natural killer (NK) cells in COX-deficient BRAFV600E melanoma cells, and NK-cell depletion accelerated tumor growth. Mechanistically, NK cells produced the chemokines XCL1 and CCL5, thereby facilitating the recruitment of cDC1 to tumors, as cDC1 express both the XCL1 receptor XCR1 and the CCL5 receptors CCR1 and CCR5. Conversely, PGE2 reduced NK-cell production of CCL5 and XCL1, and reduced NK-cell survival, thereby preventing cDC1 recruitment. Similarly, blocking CCL5 and XCL1 reduced cDC1 accumulation in vivo, whereas expressing CCL5 and XCL1, in tumors that do not express PGE2, increased cDC1 accumulation in the TME and suppressed tumor growth. However, expression of CCL5 and XCL1 was not sufficient to recruit cDC1 in PGE2-producing tumors, in part due to a PGE2-mediated downregulation of XCR1. Analysis of data from The Cancer Genome Atlas revealed that the NK cell and cDC1 gene signatures were associated with expression of XCL1, XCL2 (a human paralog of XCL1), and CCL5, and these signatures were linked to extended patient survival. Altogether, these findings reveal a mechanism by which NK cells facilitate cDC1 recruitment to promote antitumor immunity, and suggest the potential for therapeutic targeting of cDC1-attracting chemokines and PGE2.
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