近日，美国纽约大学医学院教授Dan R. Littman及其研究组揭示了微生物诱导的T细胞可塑性使免疫介导的肿瘤控制成为可能。这一研究成果发表在2026年1月14日出版的国际学术期刊《自然》上。

在这里，研究小组研究了一种肠道共生微生物，分段丝状细菌（SFB），它在小肠固有层（SILP）17中诱导抗原特异性T辅助17 （T_H17）细胞效应程序，以研究这种微生物的定植如何影响ICB抑制与SFB共享抗原的肿瘤远端生长的效果。该研究组发现，抗程序性细胞死亡蛋白1 （PD-1）治疗仅在SFB定植小鼠时才能有效抑制植入的表达SFB抗原的黑色素瘤的生长。通过T 细胞受体（TCR）克隆谱系追踪、命运定位和肽-主要组织相容性复合体（MHC）四聚体染色，该课题组人员鉴定了SFB在SILP中定植诱导的稳态T_H17细胞衍生的肿瘤相关的SFB特异性T辅助1 （T_H1）样细胞。这些受肠道教育的前T_H17细胞在肿瘤微环境（TME）中产生高水平的促炎细胞因子干扰素(IFN)-γ和肿瘤坏死因子（TNF），增强抗原呈递，促进CD8⁺肿瘤浸润细胞毒性淋巴细胞的募集、扩张和效应功能，从而实现抗PD-1介导的肿瘤控制。条件消融SFB诱导的IL-17A⁺CD4⁺ T细胞（肿瘤相关T_H1样细胞的前体），消除抗PD-1介导的肿瘤控制，并显着损害肿瘤特异性CD8⁺ T细胞招募和TME内的效应功能。他们的数据，作为一个原理的证明，定义了一个细胞途径，通过这个途径，一个单一的，确定的肠道共生印记T细胞可塑性增强了PD-1阻断，并表明微生物群的靶向调节是扩大ICB疗效的一种策略。

据了解，利用免疫系统靶向并消灭肿瘤细胞的疗法已经彻底改变了癌症治疗。免疫检查点阻断（ICB），通过抑制T细胞激活在一部分癌症患者中非常成功。然而，很大一部分人对治疗没有反应，强调需要了解影响ICB治疗效果的因素。肠道微生物群由居住在胃肠道中的数万亿微生物组成，已成为免疫功能和对癌症免疫治疗反应的关键决定因素，几项研究表明微生物群组成与临床反应有关。然而，肠道共生菌如何影响ICB疗效的机制理解仍然是未知的。

附：英文原文

Title: Microbiota-induced T cell plasticity enables immune-mediated tumour control

Author: Najar, Tariq A., Hao, Yuan, Hao, Yuhan, Romero-Meza, Gabriela, Dolynuk, Alexandra, Almo, Emma, Littman, Dan R.

Issue&Volume: 2026-01-14

Abstract: Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of Tcell activation1,2,3, is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB4,5,6,7,8,9. The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response10,11,12,13,14,15,16. However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (T_H17) cell effector program in the small intestine lamina propria (SILP)17, to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through Tcell receptor (TCR) clonal lineage tracing, fate mapping and peptide–major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (TH1)-like cells derived from the homeostatic TH17 cells induced by SFB colonization in the SILP. These gut-educated ex-TH17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A+CD4+ T cells, precursors of tumour-associated TH1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8+ Tcell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints Tcell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.

DOI: 10.1038/s41586-025-09913-z

Source: https://www.nature.com/articles/s41586-025-09913-z