LAUSR

Innate Lymphoid Cells (ILCs) play a key role in tissue mediated immunity and can be controlled by co-receptor 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 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, granzyme B and K. Furthermore, PD1 deficient Tbet+NK1.1− ILCs contributed towards diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate anti-tumor responses of Tbet+NK1.1−ILCs within the tumor microenvironment. Highlights Tbet+NK1.1− ILCs are found in WT and PD1 ko mice PD-1 is expressed on Tbet+NK1.1− ILC1s within multiple TME PD-1 controls the proliferation and function of Tbet+NK1.1− ILCs within the tumor microenvironment by modulating fatty acid metabolism. PD-1 regulates the proliferation of human Tbet+ ILC1s in human cutaneous squamous cell carcinoma (cSCC) and melanoma tumor microenvironment.