Abstract 2638: Sensitizing immunotherapy-refractory prostate cancer to immune checkpoint blockade therapy with optimized ketogenic diet regimens

Abstract The purpose of this study is to investigate strategies for enhancing immune checkpoint blockade (ICB) therapy in prostate cancer (PCa). To achieve this, we established a series of ICB-resistant PCa cell lines derived from a previously sensitive cell line, which originated from a murine model of metastatic PCa. Notably, we observed a reduction in major histocompatibility complex (MHC) class I protein levels in the resistant sublines. Our study demonstrated synergistic efficacy through the combination of anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or β-hydroxybutyrate (BHB) supplementation. Importantly, these interventions significantly delayed PCa tumor progression. Furthermore, our analysis revealed that the effects of these interventions were contingent on both BHB and adaptive immunity. In-depth single-cell transcriptomic and proteomic profiling unveiled mechanisms involving cancer-cell-intrinsic changes (upregulated MHC class I molecules) and extrinsic factors, including CD8+ T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, and reduced neutrophil presence. In conclusion, our findings provide valuable insights into the potential clinical utility of combining HDACi and optimized ketogenic diet regimens to enhance ICB therapy for PCa. Citation Format: Sean Murphy, Sharif Rahmy, Dailin Gan, Jun Li, Xuemin Lu, Xin Lu. Sensitizing immunotherapy-refractory prostate cancer to immune checkpoint blockade therapy with optimized ketogenic diet regimens [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 2638.