IFN‐γ–STAT1‐mediated NK2R expression is involved in the induction of antitumor effector CD8+ T cells in vivo

Abstract

AbstractThe induction of antitumor effector T cells in the tumor microenvironment is a crucial event for cancer immunotherapy. Neurokinin receptor 2 (NK2R), a G protein‐coupled receptor for neurokinin A (NKA), regulates diverse physiological functions. However, the precise role of NKA–NK2R signaling in antitumor immunity is unclear. Here, we found that an IFN‐γ–STAT1 cascade augmented NK2R expression in CD8+ T cells, and NK2R‐mediated NKA signaling was involved in inducing antitumor effector T cells in vivo. The administration of a synthetic analog of double‐stranded RNA, polyinosinic–polycytidylic acid (poly I:C), into a liver cancer mouse model induced type I and type II IFNs and significantly suppressed the tumorigenesis of Hepa1‐6 liver cancer cells in a STAT1‐dependent manner. The reduction in tumor growth was diminished by the depletion of CD8+ T cells. IFN‐γ stimulation significantly induced NK2R and tachykinin precursor 1 (encodes NKA) gene expression in CD8+ T cells. NKA stimulation combined with anti‐CD3 monoclonal antibody (mAb) treatment significantly augmented IFN‐γ and granzyme B production by CD8+ T cells compared with the anti‐CD3 mAb alone in vitro. ERK1/2 phosphorylation and IκBα degradation in activated CD8+ T cells were suppressed under NK2R deficiency. Finally, we confirmed that tumor growth was significantly increased in NK2R‐deficient mice compared with that in wild‐type mice, and the antitumor effects of poly I:C were abolished by NK2R absence. These findings suggest that IFN‐γ–STAT1‐mediated NK2R expression is involved in the induction of antitumor effector T cells in the tumor microenvironment, which contributes to the suppression of cancer cell tumorigenesis in vivo. In this study, we revealed that IFN‐γ–STAT1‐mediated NK2R expression is involved in the induction of antitumor effector CD8+ T cells in the tumor microenvironment, which contributes to suppressing the tumorigenesis of liver cancer cells in vivo.