Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition

作者：McKenzie Crist, Benyamin Yaniv, Sarah M. Palackdharry, Maria A. Lehn, Mario Medvedovic, Timothy M. Stone, Shuchi Gulati, Vidhya Karivedu, Michael T. Borchers, Bethany Fuhrman, Audrey Crago, Joseph Curry, Ubaldo Martinez‐Outschoorn, Vinita Takiar, Trisha Michel Wise-Draper · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2022-005632 · 被引用次数：74 · 研究领域：Immune Cell Function and Interaction、Metabolism, Diabetes, and Cancer、Immune cells in cancer

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692). METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses. RESULTS: Increased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigen...