NKG2D signaling regulates IL-17A-producing γδT cells to promote cancer progression

Abstract

{gamma}{delta}T cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance and homeostasis. {gamma}{delta}T cell activation is mediated by the T cell receptor composed of {gamma} and {delta} chains, as well as activating receptors for stress-induced ligands, such as NKG2D. Contrary to the well-established anti-tumor function of {gamma}{delta}T cells, recent studies have shown that {gamma}{delta}T cells can promote tumor development in certain contexts. However, the mechanisms leading to this diseasepromoting role remain poorly understood. Here, we show that mice lacking {gamma}{delta}T cells survive longer in a mouse model of intestinal cancer, further supporting their pro-tumoral role. In a surprising conceptual twist, we found that these pro-tumor {gamma}{delta}T cells are regulated by NKG2D signaling, a receptor normally associated with cancer cell killing. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of {gamma}{delta}T cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduces the capability of {gamma}{delta}T cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increases the frequency of {gamma}{delta}T cells. Together, these data support the hypothesis that in a tumor microenvironment where NKG2D ligands are constitutively expressed, {gamma}{delta}T cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.