Zhu Zhuxian, Huang Jianguo, Zhang Yanling, Hou Weiwei, Chen Fei, Mo Yin-Yuan, Zhang Ziqiang
Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
Earle A. Chiles Research Institute, a division of Providence Cancer Institute, Portland, OR 97213, USA.
Cell Rep. 2024 Jun 25;43(6):114306. doi: 10.1016/j.celrep.2024.114306. Epub 2024 May 30.
Gut Akkermansia muciniphila (Akk) has been implicated in impacting immunotherapy or oncogenesis. This study aims to dissect the Akk-associated tumor immune ecosystem (TIME) by single-cell profiling coupled with T cell receptor (TCR) sequencing. We adopted mouse cancer models under anti-PD-1 immunotherapy, combined with oral administration of three forms of Akk, including live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc_1100 (Amuc). We show that live Akk is most effective in activation of CD8 T cells by rescuing the exhausted type into cytotoxic subpopulations. Remarkably, only live Akk activates MHC-II-pDC pathways, downregulates CXCL3 in Bgn(+)Dcn(+) cancer-associated fibroblasts (CAFs), blunts crosstalk between Bgn(+)Dcn(+) CAFs and PD-L1(+) neutrophils by a CXCL3-PD-L1 axis, and further suppresses the crosstalk between PD-L1(+) neutrophils and CD8 T cells, leading to the rescue of exhausted CD8 T cells. Together, this comprehensive picture of the tumor ecosystem provides deeper insights into immune mechanisms associated with gut Akk-dependent anti-PD-1 immunotherapy.
肠道嗜黏蛋白阿克曼氏菌（Akk）被认为与免疫治疗或肿瘤发生有关。本研究旨在通过单细胞分析结合T细胞受体（TCR）测序来剖析与Akk相关的肿瘤免疫生态系统（TIME）。我们采用了抗PD-1免疫治疗下的小鼠癌症模型，并联合口服三种形式的Akk，包括活的Akk、巴氏杀菌的Akk（Akk-past）或其膜蛋白Amuc_1100（Amuc）。我们发现，活的Akk通过将耗竭型CD8 T细胞拯救为细胞毒性亚群，在激活CD8 T细胞方面最为有效。值得注意的是，只有活的Akk激活MHC-II-pDC途径，下调Bgn(+)Dcn(+)癌症相关成纤维细胞（CAF）中的CXCL3，通过CXCL3-PD-L1轴减弱Bgn(+)Dcn(+) CAF与PD-L1(+)中性粒细胞之间的串扰，并进一步抑制PD-L1(+)中性粒细胞与CD8 T细胞之间的串扰，从而拯救耗竭的CD8 T细胞。总之，肿瘤生态系统的这一全面图景为与肠道Akk依赖性抗PD-1免疫治疗相关的免疫机制提供了更深入的见解。
