Paradoxical pro-tumor functions of dendritic cells on colorectal cancer

Abstract

Abstract The immune system’s ability to eradicate cancer requires coordination between innate and adaptive immune cells. No other cell type bridges innate and adaptive immunity better than the dendritic cell (DC). For this reason, DCs, specifically the Batf3-dependent DC subset, are thought to be key to anti-tumor immunity. Although the anti-tumor functions of Batf3-dependent DCs have been well described in skin cancer, whether these DCs have similar anti-tumor functions in other cancers is unknown. Here we investigated the roles of Batf3-dependent DCs in colon cancer and paradoxically found that these DCs actually promote colon tumorigenesis. Thus, in a spontaneous colorectal cancer mouse model, loss of Batf3-dependent DCs resulted in decreased colon tumor number. Although Batf3-dependent DCs are best known for expanding IFNγ-producing T cells, in colon tumors, we surprisingly found that Batf3-dependent DCs were required to expand tumor-infiltrating γδT cells producing IL-17. IL-17 is known to promote colon tumorigenesis and our findings pinpoint IL-17-producing γδT cells as a key source of IL-17 for tumor growth, and surprisingly describe a requirement for Batf3-dependent DCs to expand an IL-17-producing T cell population. In addition, we identified tumor-infiltrating Batf3-dependent DCs uniquely upregulate high levels of PD-L1as a second mode of action to promote colon cancer. PD-L1 upregulation and high PD-L1 expression on Batf3-dependent DCs was specific within the tumor microenvironment. Collectively, these paradoxical pro-tumorigenic functions of Batf3-dependent DCs suggest that these DCs are not universally anti-tumor and that targeted therapies that modulate Batf3-dependent DCs could benefit colon cancer patients.