The tumor microenvironment metabolome inhibits NK cell persistence through ER stress-mediated apoptosis 4182

Description Natural Killer (NK) cells are cytotoxic innate lymphocytes that perform antigen-independent recognition and elimination of cancerous cells. While human NK cells have shown promising activity in liquid cancer, their efficacy is reduced by limited in vivo persistence and dysfunction in solid tumors. To determine the mechanisms that inhibit human NK cell functions in solid tumors, we performed an unbiased single-cell RNA sequencing analysis of patient-matched tumor and adjacent normal tissues from eight solid human cancers. Our analyses revealed that tumor-infiltrating human NK cells exhibit a marked induction of unfolded protein response (UPR) genes, suggesting that endoplasmic reticulum (ER) stress is a critical pathway induced in human NK cells in the tumor microenvironment. Human tumor-infiltrating NK cells displayed unique regulomes, and multiomic analyses identified FLI1 as an epigenetic repressor of pro-survival ER stress genes in activated NK cells. CRISPR-mediated activation of FLI1 inhibited human NK cell survival in the presence of the tumor microenvironment metabolome, and FLI1 deletion in NK cells resulted in improved solid tumor control in both mouse and human cancer models. These results suggest that the tumor microenvironment metabolome is critical in limiting the persistence of NK cells in solid tumors, introducing new strategies for enhancing the survival of activated human NK cells in cancer immunotherapy. Funding Sources Supported by T32AI007323 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)