德国弗莱堡大学Bertram Bengsch研究小组发现，CTLA-4检查点治疗的疗效依赖于IL-21信号通路介导PD-1⁺CD8⁺ T细胞的细胞毒性重编程。相关论文于2024年12月19日在线发表在《自然—免疫学》杂志上。

研究人员表示，抗程序性细胞死亡蛋白1（PD-1）和抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）治疗的疗效机制尚不完全了解。

研究人员通过免疫谱分析来自晚期黑色素瘤患者的PD-1⁺CD8⁺ T细胞（T_Resp）群体，发现组合治疗使T_Resp细胞的编程从耗竭型转向更具细胞毒性的效应型程序。这一效果在单独使用抗PD-1治疗时并未发生。

研究人员通过单细胞转录组和T细胞受体库分析，识别了扩增的PD-1⁺CD8⁺ T细胞克隆在效应程序中的变化，具体表现为不同的调控基因使用、STAT1和STAT3的利用，以及与抗肿瘤特异性相关的IL-21信号通路。这在组合治疗和抗CTLA-4单药治疗中均有表现。B16F10黑色素瘤模型中的CTLA-4阻断治疗在Il21r⁻缺失或抗IL-21受体阻断的情况下失效。

综上所述，这些结果表明IL-21信号通路对T_Resp细胞的作用对抗CTLA-4基础的检查点治疗至关重要，并突出显示了抗PD-1单药治疗的主要信号通路差异。

附：英文原文

Title: Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells

Author: Zhang, Zhen, Langenbach, Marlene, Sagar, Sagar, Fetsch, Viktor, Stritzker, Jonas, Severa, Elizabeth, Meng, Ke, Winkler, Frances, Rana, Nisha, Zoldan, Katharina, Godbole, Ira, Solis, Sabrina, Weber, Jeffrey S., Rafei-Shamsabadi, David, Lehr, Saskia, Diehl, Rebecca, Venhoff, Ana Cecilia, Voll, Reinhard E., Buettner, Nico, Neumann-Haefelin, Christoph, Boettler, Tobias, Hofmann, Maike, Boerries, Melanie, Meiss, Frank, Zeiser, Robert, Thimme, Robert, Herati, Ramin S., Bengsch, Bertram

Issue&Volume: 2024-12-19

Abstract: The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1+CD8+ T (TResp) cell populations from patients with advanced melanoma, we identified differential programming of TResp cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1+CD8+ T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specificity connected to interleukin (IL)-21 signaling in combination and anti-CTLA-4 monotherapy. Therapeutic efficacy of CTLA-4 blockade was lost in B16F10 melanoma models with either Il21r deficiency or anti-IL-21 receptor blockade. Together, these results show how IL-21 signaling to TResp is critical for anti-CTLA-4-based checkpoint therapies and highlight major signaling differences to anti-PD-1 monotherapy.

DOI: 10.1038/s41590-024-02027-0

Source: https://www.nature.com/articles/s41590-024-02027-0