The Roles of Natural Killer Cells in Breast Cancer Pathobiology and Their Regulation by Estrogens

Breast cancer remains the most commonly diagnosed malignancy among women worldwide. While breast cancer treatment outcomes have improved in recent years, there remains an unmet medical need for therapeutics that can be used with curative intent in the most aggressive breast cancer subtypes and for those cancers that have metastasized. In recent years, the success of T-cell-based therapies and other technologies that boost antitumor activities of immune cells have increased interest in using natural killer (NK) cell-based immunotherapies to treat solid tumors. These innate lymphoid cells can identify and eliminate tumor cells through their intrinsic cytotoxic activities and their ability to modulate the immune response through cytokine production. Owing to their lack of T-cell receptors, NK cells can also be used in the allogeneic setting, and strategies to develop and establish NK cells as therapeutics in breast cancer are currently being explored. In this review, we describe NK cell biology as it relates to breast cancer pathobiology and treatment outcomes and discuss how NK cell biology can be exploited and manipulated in the development of new therapeutics for breast cancer. Additionally, we review the role of estrogens in regulating NK cell activity and discuss how endocrine therapies targeting the estrogen receptor signaling axis could be employed as an approach to increase tumor immunity and the efficacy of NK-cell-directed immunotherapies.