Abstract 2096: Natural killer cells inhibit CD4+ T cell mediated IL-9 production in head and neck Cancer

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer in the world, yet 5 year survival remains poor for those with recurrence despite advances in treatment such as immunotherapy. Checkpoint blockade substantially improved survival in ~20% of recurrent and/or metastatic HNSCC patients. However, given the lack of efficacy in most patients, and the known immunosuppressive nature of HNSCC, exploring other potential immune cell therapeutic targets is of interest. Decreased natural killer (NK) as well as increased immunosuppressive CD4+ regulatory T cells (Tregs) in both peripheral blood and the tumor microenvironment are associated with a poor prognosis in HNSCC. We discovered that the anti-diabetes drug, metformin, which is also known to improve immune cell function, not only increases peripheral NK cells in HNSCC patients to the level of healthy controls, but also suppresses IL-9 secretion from NK cells. IL-9 has been implicated as a driving factor in allergic disease, a poor prognosis factor in hematologic malignancies, and an enhancer of T-reg immunosuppressive abilities. However, the function of IL-9 in solid tumors is poorly understood. Interestingly, upon depletion of CD56+ NK and NKT cells from peripheral blood mononuclear cells (PBMCs), there was a significant increase of IL-9 secretion. This effect was negated upon depletion of CD4+ T cells suggesting that NK cells may directly or indirectly inhibit CD4+ T cell IL-9 production. In order to understand potential consequences of IL-9 overproduction, we subjected HNSCC cell lines, which we demonstrated express IL9 receptor, to exogenous IL-9 which resulted in enhanced proliferation. We also found that IL-9 plasma levels are high in HNSCC patients compared to healthy controls corroborating a potential tumorigenic role for IL-9. In order to elucidate potential mechanism(s) by which NK/NKT cells regulate CD4+ T cell production, we performed single-cell RNAseq on PBMCs upon NK and NKT cell depletion. We also performed flow cytometry to identify specific CD4+ cell types responsible for increased IL-9 production and the consequential changes in other immune cell phenotypes upon the absence of NK/NKT cells. Understanding the role of IL-9 in HNSCC will be important for utilizing IL-9 as a potential marker for HNSCC prognosis as well as a possible target for future immunotherapy approaches. Citation Format: McKenzie Crist, Maria Lehn, Vinita Takiar, Trisha Wise-Draper. Natural killer cells inhibit CD4+ T cell mediated IL-9 production in head and neck Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2096.