Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite.

The gut microbiome serves as a crucial mediator for improving the efficacy of immune checkpoint blockade (ICB) therapy. Here, we show that oral supplementation with prebiotics (mannose) retarded tumor growth in immunocompetent mice in a gut microbiota dependent manner, correlating with the enrichment of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME) characterized by an increase percentage of effector and memory CD8+T cells, accompanied by a prominent immunoreactivegeneexpressionsignature. Most importantly, mannose modulates the stemness program of CD8+T cells and facilitates the generation of progenitor exhausted CD8+T cells (Tpex). Mechanistically, mannose increases gut microbial production of the short-chain fatty acids (SCFA) propionate and butyrate. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Mannose synergized with PD-1 blockade in tumor regression and augmented intratumoral Tpex differentiation into intermediate exhausted CD8+T cells (Tex-int) and terminally exhausted CD8+T cells (Tex-term). Moreover, we identified a mannose-therapy related gene signature associated with favorable responses to ICB in pan-cancer. Overall, our findings support the rationale for combining dietary supplementation of mannose with anti-PD-1 immunotherapy in ovarian cancer, and its clinical translation. Overall design: Comparative gene expression profiling analysis of RNA-seq data for tumor tissues and sorted CD8+T cells from HM1 tumors with the supplementation of mannose or not.

肠道微生物组是提升免疫检查点阻断（immune checkpoint blockade, ICB）治疗疗效的关键介导因子。本研究证实，经口补充益生元甘露糖（mannose）可通过肠道菌群依赖的方式延缓免疫健全小鼠的肿瘤生长，该效应与粪杆菌属（Faecalibaculum）的菌群富集密切相关。甘露糖可塑造免疫刺激性肿瘤微环境（tumor microenvironment, TME），其特征为效应性与记忆性CD8+T细胞占比升高，并伴随显著的免疫反应性基因表达特征。最为关键的是，甘露糖可调控CD8+T细胞的干性程序，并促进祖细胞样耗竭CD8+T细胞（progenitor exhausted CD8+T cells, Tpex）的生成。从机制层面而言，甘露糖可提升肠道微生物合成短链脂肪酸（short-chain fatty acids, SCFA）丙酸与丁酸的能力。给予丙酸与丁酸可抑制肿瘤进展，并在体内外均能促进Tpex的扩增与分化。甘露糖可与PD-1阻断剂协同促进肿瘤消退，并增强瘤内Tpex向中间耗竭CD8+T细胞（intermediate exhausted CD8+T cells, Tex-int）与终末耗竭CD8+T细胞（terminally exhausted CD8+T cells, Tex-term）的分化。此外，本研究鉴定出了与泛癌中ICB良好应答相关的甘露糖治疗相关基因特征。综上，本研究结果支持将膳食补充甘露糖与抗PD-1免疫治疗联合应用于卵巢癌的理论依据，且具备临床转化潜力。整体实验设计：对补充甘露糖与否的HM1肿瘤组织及分选得到的CD8+T细胞的RNA测序（RNA-seq）数据进行比较基因表达谱分析。