Abstract 3507: β-Hydroxy-β-methylbutyrate (HMB) sensitizes murine pancreatic ductal adenocarcinoma (PDAC) to immunotherapy

Abstract

Abstract Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. PDAC often presents at advanced tumor stages, resulting in poor survival rates. Immunotherapies such as inhibition of programmed death 1 (PD1) are effective in many cancers, but not in PDAC. HMB is a leucine metabolite that reduces PDAC progression and cachexia in association with enhanced antitumor immune responses. The purpose of this study was to determine if HMB treatment enhances immunotherapeutic response in PDAC. Methods: C57BL/6J mice bearing subcutaneously transplanted PANC02 tumors were fed either a control (AIN93G) or HMB (1% w/w) supplemented diet. Once tumors were palpable, mice were randomized for treatment with vehicle or anti-PD1 immunotherapy (n=12-13/group). Tumors were harvested and global transcriptomic analysis was performed. Results: Both HMB and anti-PD1 interventions alone were insufficient to reduce tumor growth. However, the combination of HMB and anti-PD1 resulted in significantly smaller tumors than the anti-PD1 alone group, indicating that HMB was able to stimulate PDAC response to ICI. Transcriptomic analysis revealed limited transcriptional effects attributable to immunosurveillance following treatment with either HMB or anti-PD1 alone; however, the combination produced a robust antitumor immune response. Digital cytometry analysis revealed altered immune cell composition in the tumor microenvironment. Conclusion: The combination of HMB with anti-PD1 treatment elicited significant antitumor responses in a murine model of PDAC progression. Given that immunotherapy trials in PDAC have not yet proven effective, even when combined with cytotoxic chemotherapy, our preclinical findings support clinical evaluation of combined ICI and HMB regimens as a therapeutic strategy against PDAC. Citation Format: Suhas K. Etigunta, Michael F. Coleman, Kristyn A. Liu, Alex J. Pfeil, Zhengrong Cui, Stephen D. Hursting. β-Hydroxy-β-methylbutyrate (HMB) sensitizes murine pancreatic ductal adenocarcinoma (PDAC) to immunotherapy [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 3507.