NK cells are capable of an array of functions that range widely from their classic anti-tumor and anti-viral cytotoxic effector functions, to their critical regulatory roles in controlling inflammatory immune responses and promoting tissue growth. However, the mechanisms that polarize NK cells to these distinct and opposing functions are incompletely understood. NK cell functional subsets are primarily identified and studied based on phenotype, which has served as an accessible means for profiling NK cells and does offer information on NK cell activation state. However, inconsistencies have emerged in using classic phenotypes to inform function, which raise the questions: Can phenotype in fact define NK cell functional fate? What factors do profile and drive NK cell fate? In other immune cells, cell metabolism has been shown to critically determine subset polarization. There is a growing body of evidence that cell metabolism is integral to NK cell effector functions. Glucose-driven glycolysis and oxidative metabolism have been shown to drive classic NK cell anti-tumor and anti-viral effector functions. Recent studies have uncovered a critical role for metabolism in NK cell development, education, and memory generation. In this review, we will draw on the evidence to date to investigate the relationship between NK cell phenotype, metabolism, and functional fate. We explore a paradigm in which the differential activity of metabolic pathways within NK cells produce distinct metabolic fingerprints that comprehensively distinguish and drive the range of NK cell functional abilities. We will discuss future areas of study that are needed to develop and test this paradigm and suggest strategies to efficiently profile NK cells based on metabolism. Given the emerging role of metabolism in driving NK cell fates, profiling and modulating NK cell metabolism holds profound therapeutic potential to tune inflammatory and regulatory NK cell responses to treat disease.
The crosstalk between NK cells and M1 macrophages has a vital role in the protection against infections and tumor development. However, macrophages in the tumor resemble an M2 phenotype, and, at present, their effect on NK cells is less clear. This study investigated whether tumor-associated macrophages (TAMs) have a role in altering NK cell function and phenotype using in vitro cocultures of murine NK cells with peritoneal or bone marrow-derived, M2-polarized macrophages or TAMs isolated from spontaneous mouse breast tumors. We report here that both peritoneal and bone marrow-derived M2 macrophages, as well as TAMs, substantially inhibit NK cell activation and concordant cytotoxicity against tumor cells. The mechanism for this inhibition was found to require contact between the respective cell types. Both M2 macrophages and TAMs are producers of the immunosuppressive cytokine TGF-β. The inhibition of TGF-β restored the cytotoxicity of NK cells in contact with M2 macrophages, implicating TGF-β in the mechanism for NK cell inhibition. In addition to affecting NK cell function, TAMs also induced a CD27CD11b-exhausted NK cell phenotype, which corresponds with the reduced activation and cytotoxicity observed. This study reveals a novel implication of TAMs in the tumor-associated inhibition of NK cell function by demonstrating their capacity to directly alter NK cell cytotoxicity and phenotype in a contact-dependent mechanism involving TGF-β. These findings identify the interaction between NK cells and TAMs as a prospective therapeutic target to enhance NK cell effector function for effective NK cell cancer therapies.
Natural killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematologic malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although rearming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56CD16 subset with activation state and antitumor functions that increase with CD56 brightness. We investigated whether these expanded NK cells may overcome the limitations of autologous NK cell therapy against solid tumors. Peripheral blood- and ascites-derived NK cells from ovarian cancer patients were expanded and then adoptively transferred into cell-line and autologous patient-derived xenograft models of human ovarian cancer. Expanded ovarian cancer patient NK cells reduced the burden of established tumors and prolonged survival. These results suggest that CD56 NK cells harbor superior antitumor function compared with CD56 cells. Thus, NK cell expansion may overcome limitations on autologous NK cell therapy by converting the patient's NK cells to a cytotoxic subset that exerts a therapeutic effect against autologous tumor. These findings suggest that the value of expanded autologous NK cell therapy for ovarian cancer and other solid malignancies should be clinically assessed. .
Metabolic flux can dictate cell fate, including immune cell effector and regulatory function. The metabolic regulation of cell function is well characterized with respect to effector, memory, and regulatory T cells. This knowledge may allow for manipulation of T cell metabolic pathways that set the stage for more effective T cell therapy. Natural Killer (NK) and T-lymphocytes have complementary roles in the defense against pathogens. However, studies of NK cell metabolism are only beginning to emerge and there is comparatively little knowledge on the metabolic regulation of NK-cell activation and effector function. Given their common lymphoid lineage, effector functions and cellular memory potential our current knowledge on T cell metabolism could inform investigation of metabolic reprogramming in NK cells. In this review, we compare the current knowledge of metabolic regulation in T cell and NK cell development, activation, effector and memory function. Commonalties in glucose transport, hypoxia-inducible factors and mTOR highlight metabolic control points in both cells types. Contrasting the glycolytic and oxidative nodes of metabolic regulation in T cells versus NK cells may provide insight into the contribution of specific immune responses to disease and promote the development of immunotherapeutic approaches targeting both innate and adaptive immune responses.
Ovarian cancer (OC) is the leading cause of gynecological cancer-related death in North America. Most ovarian cancer patients (OCPs) experience disease recurrence after first-line surgery and chemotherapy; thus, there is a need for novel second-line treatments to improve the prognosis of OC. Although peripheral blood-derived NK cells are known for their ability to spontaneously lyse tumour cells without prior sensitization, ascites-derived NK cells (ascites-NK cells) isolated from OCPs exhibit inhibitory phenotypes, impaired cytotoxicity and may play a pro-tumourigenic role in cancer progression. Therefore, it is of interest to improve the cytotoxic effector function of impaired OCP ascites-NK cells at the tumour environment. We investigated the efficacy of using an artificial APC-based ex vivo expansion technique to generate cytotoxic, expanded NK cells from previously impaired OCP ascites-NK cells, for use in an autologous model of NK cell immunotherapy. We are the first to obtain a log-scale expansion of OCP ascites-NK cells that upregulate the surface expression of activating receptors NKG2D, NKp30, NKp44, produce robust amounts of anti-tumour cytokines in the presence of OC cells and mediate direct tumour cytotoxicity against ascites-derived, primary OC cells obtained from autologous patients. Our findings demonstrate that it is possible to generate cytotoxic OCP ascites-NK cells from previously impaired OCP ascites-NK cells, which presents a promising immunotherapeutic target for the second-line treatment of OC. Future work should focus on evaluating the in vivo efficacy of autologous NK cell immunotherapy through the intraperitoneal delivery of NK cell expansion factors to a preclinical xenograft mouse model of human OC.
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