Abstract 3859: HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma

Abstract

Abstract Accumulating evidence suggests that failure of antitumor immunity may be due to dysregulation of energy metabolism. Head and neck squamous cell carcinoma (HNSCC) exhibits increased activity of two key enzymes, pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), which are central to the glycolytic pathway responsible for the conversion of glucose to ATP energy. HSP90 is a molecular chaperone that plays a critical role in the folding, stabilization, and regulation of a wide range of client proteins involved in various cellular processes, including metabolism. However, whether HSP90 signaling contributes to tumor metabolism rewiring and antitumor immune response remains unknown. Using ganetespib as a drug model for HSP90 inhibition and combining results from clinical trials and animal treatment, our study demonstrated that HSP90 inhibition causes an obstruction of glycolytic flux in HNSCC cells by simultaneously suppressing both PKM2 and PFKP at the transcriptional and post-translational levels. In addition, ganetespib enhances T cell-driven antitumor immune responses by promoting CD8+ T cell infiltration into the tumor. Mechanistically, ganetespib downregulates IL8 signaling by inhibiting PKM2 and PFKP-mediated glycolysis in HNSCC cells, which in turn contributes to ganetespib-mediated T cell tumor infiltration. These findings provide a novel molecular basis for the use of effective HSP90 inhibitors to improve the outcome of HNSCC patients. Citation Format: Fanghui Chen, Chris Tang, Fan Yang, Asari Ekpenyong, Richard Qin, Nabil F. Saba, Yong Teng. HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3859.