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

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.