Abstract B020: Hypoxia as tumor-intrinsic regulator of Flt3L production by NK cells

Abstract

Natural killer (NK) cell abundance in the tumor correlates with increased immunotherapy responses and better survival in cancer patients. As their name suggests, NK cells can control tumors through their direct cytotoxicity, but also play an important part in regulating immune responses through their immunomodulatory production of cytokines and chemokines. We recently discovered that NK cells control immunotherapy responses through their production of a cytokine called FMS-like tyrosine kinase 3 ligand (Flt3L) in the tumor, which regulates type 1 conventional dendritic cell (cDC1) abundance. However, the mechanisms regulating NK cell phenotype and function, including Flt3L production, in the tumor remain unknown. Here, we define tumor cell-intrinsic mechanisms that control these protective NK cell functions in the tumor. Across eight mouse melanoma tumor models, we found two genetically distinct murine ectopic tumors (referred to as Mel1 and Mel2) that are similarly infiltrated with total NK cells, but have distinct skewing of NK cell phenotypes and differential production of Flt3L, correlating with differences in cDC1 abundance. Pathway analysis of differentially expressed genes in tumor cells from these two models found a significant increase in hypoxia signaling in Mel1 tumors. Using an in vivo hypoxia tracer and in vitro hypoxia chamber studies, we found that NK cells in Mel1 tumors experience more severe hypoxia and that NK cells produce significantly less Flt3L under hypoxic conditions (1% O2) compared to NK cells in normoxic conditions (21% O2). Our findings suggest that hypoxia is a tumor-intrinsic regulator of Flt3L production by NK cells and highlight a previously unknown inhibitory pathway within the tumor that can shape the protective immunomodulatory effects of NK cells.

Citation Format: Renske J.E. van den Bijgaart, Shayan C. Avanessian, Nayvin W. Chew, Thao T. Tang, Kevin C. Barry. Hypoxia as tumor-intrinsic regulator of Flt3L production by NK cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B020.