Defining mechanisms of NK cell dysfunction in the multiple myeloma tumor microenvironment 9377

Description NK cells are cytotoxic cells that have intrinsic ability to mediate anti-tumor responses. However, the immunosuppressive tumor microenvironment (TME) can limit their efficacy. Multiple myeloma (MM) is a hematologic malignancy that produces metabolites, including lactic acid (LA), in the TME. How LA affects NK cell function remains poorly understood. In this study, we hypothesized that high LA in the TME (15 mM) inhibits NK cell functionality. To test this, primary human conventional NK (cNK) cells were exposed to varying concentrations of LA and assessed for cytotoxicity against tumor targets, proliferation, and cytokine production in vitro. We observed that IFN-g production (P = 0.0035) and degranulation, measured via CD107a (p = 0.0018) by cNK cells significantly decreased under 15mM LA treatment conditions compared to controls. Approximately 40% of cNK cells proliferated under control conditions (0 or 3 mM LA), while 15 mM LA abrogated proliferation. We also studied the role of cytokine-induced memory-like (ML) NK cells. ML differentiation resulted in partial rescue of LA-induced reductions in IFN-g production (p = 0.0417) observed in cNK cells. Despite this, ML NK cells still exhibited reduced IFN-g and degranulation responses in 15 mM LA, compared to control conditions. These data suggest that LA is a metabolic checkpoint on NK cells, and ML differentiation and strategies to insulate NK cells from LA effects, may improve NK cell anti-tumor responses.