Programmed cell death-1 receptor-mediated regulation of Tbet⁺NK1.1^- innate lymphoid cells within the tumor microenvironment.

Abstract

Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet⁺NK1.1^- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet⁺NK1.1^- ILCs. PD-1 significantly controlled the proliferation and function of Tbet⁺NK1.1^- ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet⁺NK1.1^- ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet⁺NK1.1^- ILCs expressed significantly increased IFNγ and granzyme B and K. Furthermore, PD-1-deficient Tbet⁺NK1.1^- ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet⁺NK1.1^- ILCs within the TME.