Intrinsic RIG-I restrains STAT5 activation to modulate anti-tumor activity of CD8+ T cells

Anti-tumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in tumor microenvironment, yet exact mechanisms remain incompletely defined. Here we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells. Mechanistically, T cell activation-induced RIG-I upregulation restrained STAT5 activation via competitively sequestering HSP90. In accordance, the frequency of RIG-I+ tumor-infiltrating CD8+ T cells in human colon cancer positively correlated with attenuated survival and effector signatures of CD8+ T cells as well as poor prognosis. Collectively, these results implicate RIG-I as a potentially druggable factor for improving CD8+ T cells-based tumor immunotherapy.