Mok Stephen, Liu Huey, Ağaç Çobanoğlu Didem, Anang Nana-Ama A S, Mancuso James J, Wherry E John, Allison James P
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2418985122. doi: 10.1073/pnas.2418985122. Epub 2025 Jan 9.
The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional - or -knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.
靶向细胞毒性T淋巴细胞相关抗原4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）的免疫检查点抑制所引起的T细胞分化对免疫记忆反应的影响仍不清楚。我们对抗CTLA-4和抗PD-1对小鼠记忆T细胞形成的影响进行的研究表明，抗CTLA-4产生的记忆T细胞比抗PD-1产生的记忆T细胞表现出更大的扩增、细胞因子产生和抗肿瘤活性。值得注意的是，抗CTLA-4在启动过程中保留了更多的T细胞因子1（TCF-1）+T细胞，而抗PD-1则导致更多的胸腺细胞选择相关高迁移率族框（TOX）+T细胞。使用条件性或基因敲除小鼠进行的实验强调，TCF-1对抗CTLA-4产生的记忆反应至关重要，而单独在T细胞中缺失TOX对抗PD-1的反应没有影响。加深我们对检查点抑制如何影响记忆反应的理解对于推进我们对这些免疫疗法对免疫系统的持久影响的理解至关重要。
