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 (PGE2) 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 PGE2 for immune evasion and that could be exploited for cancer therapy.,•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 PGE2 impairs NK cell and cDC1 resulting in cancer immune evasion,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 PGE2 impairs NK cell and cDC1 resulting in cancer immune evasion,Natural killer cells recruit dendritic cells to the tumor microenvironment, and disruption of this process results in cancer immune evasion.
The question whether tumorigenic cancer stem cells exist in human melanomas has arisen recently1.,Here we show that in melanomas, tumor stem cells (MTSC) can be isolated prospectively as a highly enriched CD271+ MTSC population using a process that maximizes viable cell transplantation1,6.,In this study the tumors sampled were taken from a broad spectrum of sites and stages.,High viability FACS isolated cells resuspended in a matrigel vehicle were implanted into T, B, and NK deficient Rag2−/− γc−/− mice (RG) mice.,The CD271+ subset of cells was the tumor initiating population in 9/10 melanomas tested.,Transplantation of isolated melanoma cells into engrafted human skin or bone in RG mice resulted in melanoma from CD271+ but not CD271− cells.,We also showed that tumors transplanted by CD271+ patient cells were capable of metastasis in-vivo.,Importantly, CD271+ melanoma cells lacked expression of TYR, MART and MAGE in 86%, 69% and 68% of melanoma patients respectively suggesting why T cell therapies directed at these antigens usually result in only temporary tumor shrinkage.