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.

The depths of PD-1 function within the tumor microenvironment beyond CD8+ T cells.

Programmed cell death-1 (PD-1; CD279) is a cell surface receptor that is expressed in both innate and adaptive immune cells. The role of PD-1 in adaptive immune cells, specifically in CD8+ T cells, has been thoroughly investigated but its significance in other immune cells is yet to be well established. This review will address the role of PD-1 based therapies in enhancing non-CD8+ T cell immune responses within cancer. Specifically, the expression and function of PD-1 in non-CD8+ immune cell compartments such as CD4+ T helper cell subsets, myeloid cells and innate lymphoid cells (ILCs) will be discussed. By understanding the immune cell specific function of PD-1 within tissue resident innate and adaptive immune cells, it will be possible to stratify patients for PD-1 based therapies for both immunogeneic and non-immunogeneic neoplastic disorders. With this knowledge from fundamental and translational studies, PD-1 based therapies can be utilized to enhance T cell independent immune responses in cancers.