Tumour Immunology: NK Cells Bring in the Troops

RESEARCH HIGHLIGHTS

Nature Reviews Immunology | Published online 16 Feb 2018; doi:10.1038/nri.2018.14

Macmillan Publishers Limited TUMOUR IMMUNOLOGY NK cells bring in the troops

The presence of conventional type 1 dendritic Xcl1 mRNA. Intracellular flow cytometry analyses cells (cDC1s) in tumours has been associated with of cells from COX-deficient tumours four days enhanced antitumour immunity, but it has been after implantation showed that NK cells expressed higher unclear what promotes their infiltration. A recent CCL5 protein and Xcl1 mRNA, while some rare expression study from Caetano Reis e Sousa and colleagues tumour-infiltrating CD8+ T cells expressed CCL5 now shows that natural killer (NK) cells recruit but not Xcl1. of NK cell cDC1s to the tumour microenvironment by cDC1s express the CCL5 receptors CCR1 and and cDC1 producing the chemokines CCL5 and XCL1. CCR5 as well as XCR1, the receptor for XCL1, signature The same authors previously reported that and the authors showed that they migrate genes in tumours suppress cDC1-dependent CD8+ T cell towards these chemokines in transwell assays. antitumour responses by producing Moreover, antibody-mediated blockade of tumour prostaglandin E2 (PGE2), and that deletion CCL5 and XCL1 in vivo markedly reduced cDC1 samples was of the cyclooxygenase (COX) enzymes that accumulation in COX-deficient tumours. Further associated are necessary for PGE2 synthesis enhances studies revealed that PGE2 reduces NK cell survival antitumour immunity. They therefore compared within tumours and inhibits their production of with increased cDC1 accumulation in the tumours of mice that CCL5 and XCL1, as well as impairing cDC1 patient were implanted with COX-deficient BRAFV600E responsiveness to these chemokines. Therefore, in survival melanoma cells or with control BRAFV600E mice, NK cells can promote antitumour immunity melanoma cells. Similar overall numbers of by recruiting cDC1s, and tumour-derived PGE2 CD45+ cells and CD11c+MHCII+ cells were found blocks this process. in COX-deficient and control tumours four days The authors analysed data sets from human after implantation, but accumulation of cDC1s haematopoietic cells and found that human was markedly increased in the COX-deficient NK cells also express CCL5 and XCL1, as well as tumours. Furthermore, cDC1s infiltrated deeper XCL2 (an XCL1 paralogue found in humans but into COX-deficient tumours and often formed not in mice). They used The Cancer Genome Atlas multicellular clusters. Enhanced cDC1 to assess whether these genes are expressed in infiltration into COX-deficient tumours was also human cancers and found a positive correlation observed in other mouse models of breast cancer between the expression of XCL1, XCL2 and CCL5 and colorectal cancer. BATF3-deficient mice in data sets for cutaneous melanoma and several (which lack cDC1 cells) were unable to suppress carcinomas. This chemokine gene expression the growth of COX-deficient tumours, and signature further correlated positively with gene this was associated with markedly reduced signatures of NK cells, cDC1s and CD8+ T cells. CD8+ T cell infiltration, indicating the functional Finally, the authors found that higher expression relevance of cDC1s for antitumour immunity. of NK cell and cDC1 signature genes in tumour An early increase in NK cell recruitment was samples was associated with increased patient also seen in COX-deficient tumours, with the survival from various skin, head and neck, breast distribution of intratumoural NK cells closely and lung cancers. matching that of cDC1s. This suggested that These findings suggest that NK cells drive NK cells may recruit cDC1s and, in agreement immunity to tumours by recruiting cDC1s that with this, genetic or antibody-mediated depletion activate CD8+ T cells and that tumour cell of NK cells (but not other lymphocytes) decreased production of PGE2 suppresses this antitumour cDC1 accumulation in COX-deficient tumours. pathway. The authors propose that strategies that Moreover, antibody-mediated depletion of drive cDC1 accumulation in tumours could NK cells led to rapid growth of COX-deficient enhance the efficacy of cancer immunotherapies. tumours in wild-type mice. The authors assessed Yvonne Bordon the levels of various NK cell-derived chemokines ORIGINAL ARTICLE Böttcher, J. P. et al. NK cells stimulate recruitment and found that COX-deficient tumours contained of cDC1 into the tumor microenvironment promoting cancer immune markedly elevated levels of CCL5 protein and control. Cell https://doi.org/10.1016/j.cell.2018.01.004 (2018)