Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer (PCa) poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens for using KD as an immunotherapy sensitizer. In this study, we established a series of ICB-resistant PCa cell lines and developed a highly effective strategy of combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or dietary supplementation of the ketone body β-hydroxybutyrate (BHB), which is an endogenous HDACi. CKD and BHB supplementation each delayed PCa tumor growth as monotherapy, and both BHB and adaptive immunity were required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that HDACi and ketogenesis enhanced ICB efficacy through both cancer cell-intrinsic mechanisms, including upregulation of MHC class I molecules, and -extrinsic mechanisms, such as CD8+ T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophil infiltration. Overall, these findings illuminate a potential clinical path of using HDACi and optimized KD regimens to enhance ICB therapy for PCa.

中文翻译：

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生酮饮食改变前列腺癌的表观遗传和免疫景观，以克服对免疫检查点阻断疗法的抵抗

对免疫检查点阻断（ICB）疗法的耐药性是限制免疫疗法疗效的巨大临床挑战。特别是，前列腺癌（PCa）由于其免疫抑制特性对 ICB 治疗提出了挑战。据报道，生酮饮食 (KD) 可增强其他一些癌症模型对 ICB 治疗的反应。然而，也观察到与连续 KD 相关的副作用，需要更好的机制理解和优化使用 KD 作为免疫治疗增敏剂的方案。在这项研究中，我们建立了一系列 ICB 耐药性 PCa 细胞系，并开发了一种高效策略，将抗 PD1 和抗 CTLA4 抗体与组蛋白脱乙酰酶抑制剂 (HDACi) 伏立诺他、循环生酮饮食 (CKD) 或饮食结合起来。补充酮体β-羟基丁酸(BHB)，它是一种内源性HDACi。作为单一疗法，CKD 和 BHB 补充均能延迟 PCa 肿瘤的生长，并且 CKD 的抗肿瘤活性需要 BHB 和适应性免疫。单细胞转录组和蛋白质组分析表明，HDACi 和生酮通过癌细胞内在机制（包括 MHC I 类分子的上调）和外在机制（如 CD8+ T 细胞化学吸引、M1/M2 巨噬细胞重新平衡、单核细胞）增强 ICB 功效。向抗原呈递细胞分化，并减少中性粒细胞浸润。总体而言，这些发现阐明了使用 HDACi 和优化的 KD 方案来增强 PCa 的 ICB 治疗的潜在临床路径。