The fate and function of NK cells in the suppressive tumor microenvironment

Abstract

Abstract Natural killer (NK) cells are an important cell subset of the innate immune system. Accumulating evidence indicates that NK cells are dysfunctional in the tumor microenvironment during cancer development. However, the dynamic changes in phenotypes and functional interactions within the tumor microenvironment during tumor development and progression are unknown. Here, we used both the mouse E0771 breast cancer and B16F0 melanoma tumor models to mimic different clinical stages of human cancers and characterized the dynamic distributions and qualities of NK cells in different organs and tumors associated with tumor progression. We found that NK cells are dynamically involved in the immune responses to cancer with different distributions and phenotypic profiles in tumor sites and other peripheral organs during the course of tumor development and progression. In the early stages of tumor development, NK cells exhibit effector properties. In the later cancer stages, NK cells have impaired cytotoxic capacities and dysfunctional states. Importantly, we found that melanoma and breast cancer cells promote NK cells to become senescent NK cells in vitro and in vivo in tumor microenvironments. These studies provide a better understanding of the dynamic and functional role of NK cells in anti-tumor immunity, which may facilitate the development of novel immunotherapies targeting NK cells for cancer treatment. the Melanoma Research Alliance, American Cancer Society, and the National Institutes of Health.