Role of the KLRG1 pathway during the immune response to cancer

Abstract

Abstract Immunotherapy drugs targeting T cells have been successfully developed for a variety of different cancers. In contrast, comparably less work has been done on targeting natural killer (NK) cells for immunotherapy. NK cells are intriguing targets for a number of different reasons, including their cytotoxic abilities and relatively lower autoimmunity risks. Thus, treatments that target NK cells, either alone or in conjunction with T cells, should be explored for the development of new treatments. One of the most well-known immunotherapy targets, programmed death-1 (PD-1) has recently been implicated in modulating NK cell function in cancer and demonstrates that targeting NK cells is an important aspect of cancer treatment. In addition to PD-1, there are many checkpoint molecules that may be capable of impacting NK cell function. One such target is KLRG1, a well conserved C-type lectin inhibitory receptor expressed on NK cells, which contains an ITIM in its cytoplasmic domain. To determine the role of KLRG1, and expand on the role of PD-1, as potential NK cell checkpoints, we developed a series of mice deficient for KLRG1 and PD-1, and took advantage of the NK sensitive cancer model B16. Following administration of B16-E-cadherin, we found that KLRG1 deficient animals had significantly fewer tumors in the lung tissue, compared to wild type controls. In addition, B16-E-cadherin resulted in a higher number of tumors in wild-type mice, compared to the parental B16 cell line. Altogether, these data suggest that KLRG1 is a checkpoint target candidate.