Abstract 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.

Programmed cell death-1 receptor mediated regulation of Tbet+ NK1.1− Innate Lymphoid Cells within the Tumor Microenvironment