Liu Nian, Chen Lihui, Yan Mingjie, Tao Qian, Wu Jie, Chen Jing, Chen Xiang, Zhang Wei, Peng Cong
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Research (Wash D C). 2023 Apr 28;6:0127. doi: 10.34133/research.0127. eCollection 2023.
Natural killer (NK) cells, as key immune cells, play essential roles in tumor cell immune escape and immunotherapy. Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients; however, the details of the mechanism remain elusive. In this study, we found that was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and that a high abundance was related to longer survival in melanoma patients. Furthermore, administration of remarkably improved the efficacy of anti-PD1 therapy and increased the overall survival of tumor-bearing mice; moreover, application of led to a significant accumulation of NK cells in the tumor microenvironment. Interestingly, conditioned medium isolated from an culture system dramatically enhanced NK cell function. Gas chromatography-mass spectrometry/ultrahigh performance liquid chromatography-tandem mass spectrometry-based metabolomic analysis showed that l-serine production was significantly decreased in the group; moreover, administration of an l-serine synthesis inhibitor dramatically increased NK cell activation, which enhanced anti-PD1 immunotherapy effects. Mechanistically, supplementation with l-serine or application of an l-serine synthesis inhibitor affected NK cell activation through Fos/Fosl. In summary, our findings reveal the role of bacteria-modulated serine metabolic signaling in NK cell activation and provide a novel therapeutic strategy to improve the efficacy of anti-PD1 immunotherapy in melanoma.
自然杀伤（NK）细胞作为关键免疫细胞，在肿瘤细胞免疫逃逸和免疫治疗中发挥着重要作用。越来越多的证据表明，肠道微生物群落会影响抗PD1免疫治疗的疗效，重塑肠道微生物群是提高晚期黑色素瘤患者抗PD1免疫治疗反应性的一种有前景的策略；然而，其机制细节仍不清楚。在本研究中，我们发现[具体细菌名称]在对抗PD1免疫治疗有反应的黑色素瘤患者中显著富集，且[具体细菌名称]的高丰度与黑色素瘤患者更长的生存期相关。此外，给予[具体细菌名称]显著提高了抗PD1治疗的疗效，并延长了荷瘤小鼠的总生存期；而且，应用[具体细菌名称]导致肿瘤微环境中NK细胞显著聚集。有趣的是，从[具体细菌名称]培养系统中分离出的条件培养基显著增强了NK细胞功能。基于气相色谱 - 质谱/超高效液相色谱 - 串联质谱的代谢组学分析表明，[具体细菌名称]组中L - 丝氨酸的产生显著减少；此外，给予L - 丝氨酸合成抑制剂显著增加了NK细胞的活化，从而增强了抗PD1免疫治疗效果。从机制上讲，补充L - 丝氨酸或应用L - 丝氨酸合成抑制剂通过Fos/Fosl影响NK细胞活化。总之，我们的研究结果揭示了细菌调节的丝氨酸代谢信号在NK细胞活化中的作用，并提供了一种新的治疗策略来提高黑色素瘤抗PD1免疫治疗的疗效。
