NK cells bring in the troops

The presence of conventional type 1 dendritic cells (cDC1s) in tumours has been associated with enhanced antitumour immunity, but it has been unclear what promotes their infiltration. A recent study from Caetano Reis e Sousa and colleagues now shows that natural killer (NK) cells recruit cDC1s to the tumour microenvironment by producing the chemokines CCL5 and XCL1.

Credit: Macmillan Publishers Limited

The same authors previously reported that tumours suppress cDC1-dependent CD8⁺ T cell antitumour responses by producing prostaglandin E2 (PGE₂), and that deletion of the cyclooxygenase (COX) enzymes that are necessary for PGE₂ synthesis enhances antitumour immunity. They therefore compared cDC1 accumulation in the tumours of mice that were implanted with COX-deficient BRAF^V600E melanoma cells or with control BRAF^V600E melanoma cells. Similar overall numbers of CD45⁺ cells and CD11c⁺MHCII⁺ cells were found in COX-deficient and control tumours four days after implantation, but accumulation of cDC1s was markedly increased in the COX-deficient tumours. Furthermore, cDC1s infiltrated deeper into COX-deficient tumours and often formed multicellular clusters. Enhanced cDC1 infiltration into COX-deficient tumours was also observed in other mouse models of breast cancer and colorectal cancer. BATF3-deficient mice (which lack cDC1 cells) were unable to suppress the growth of COX-deficient tumours, and this was associated with markedly reduced CD8⁺ T cell infiltration, indicating the functional relevance of cDC1s for antitumour immunity.

An early increase in NK cell recruitment was also seen in COX-deficient tumours, with the distribution of intratumoural NK cells closely matching that of cDC1s. This suggested that NK cells may recruit cDC1s and, in agreement with this, genetic or antibody-mediated depletion of NK cells (but not other lymphocytes) decreased cDC1 accumulation in COX-deficient tumours. Moreover, antibody-mediated depletion of NK cells led to rapid growth of COX-deficient tumours in wild-type mice. The authors assessed the levels of various NK cell-derived chemokines and found that COX-deficient tumours contained markedly elevated levels of CCL5 protein and Xcl1 mRNA. Intracellular flow cytometry analyses of cells from COX-deficient tumours four days after implantation showed that NK cells expressed CCL5 protein and Xcl1 mRNA, while some rare tumour-infiltrating CD8⁺ T cells expressed CCL5 but not Xcl1.

cDC1s express the CCL5 receptors CCR1 and CCR5 as well as XCR1, the receptor for XCL1, and the authors showed that they migrate towards these chemokines in transwell assays. Moreover, antibody-mediated blockade of CCL5 and XCL1 in vivo markedly reduced cDC1 accumulation in COX-deficient tumours. Further studies revealed that PGE₂ reduces NK cell survival within tumours and inhibits their production of CCL5 and XCL1, as well as impairing cDC1 responsiveness to these chemokines. Therefore, in mice, NK cells can promote antitumour immunity by recruiting cDC1s, and tumour-derived PGE₂ blocks this process.

higher expression of NK cell and cDC1 signature genes in tumour samples was associated with increased patient survival

The authors analysed data sets from human haematopoietic cells and found that human NK cells also express CCL5 and XCL1, as well as XCL2 (an XCL1 paralogue found in humans but not in mice). They used The Cancer Genome Atlas to assess whether these genes are expressed in human cancers and found a positive correlation between the expression of XCL1, XCL2 and CCL5 in data sets for cutaneous melanoma and several carcinomas. This chemokine gene expression signature further correlated positively with gene signatures of NK cells, cDC1s and CD8⁺ T cells. Finally, the authors found that higher expression of NK cell and cDC1 signature genes in tumour samples was associated with increased patient survival from various skin, head and neck, breast and lung cancers.

These findings suggest that NK cells drive immunity to tumours by recruiting cDC1s that activate CD8⁺ T cells and that tumour cell production of PGE₂ suppresses this antitumour pathway. The authors propose that strategies that drive cDC1 accumulation in tumours could enhance the efficacy of cancer immunotherapies.