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 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 IFNg, granzyme B and K. Furthermore, PD-1 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. Overall design: Tumour Infiltrating Lymphocytes were isolated using ficol density gradient centrifugation. Cells were then debulked with Thy1 microbeads and then stained with sample tags and Abseq antibodies along with Lineage cocktail antibodies and Thy1. Lin-Thy1+ cells were enriched through flow sorting and then loaded onto two cartridges and subjected to Rhapsody analysis.