PD-1 blockade during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion

In cancer, CD8+ T cell responses are dominated by exhausted T cells, which can be reinvigorated using immune checkpoint blockade therapy and can control large tumors. However, it remains unclear which T cell fate best supports long-term immunity following tumor regression or clearance and a period of minimal antigen load. This question is particularly relevant following surgical tumor resection, when tuning the immune system could prevent recurrence. To determine which T cell fate provides durable protection following surgery and metastatic rechallenge, we modulated T cell priming using anti-PD-1, IFN-β or agonistic anti-CD40 and assessed effects on CD8+ T cell differentiation and overall survival. IFN-β and anti-CD40 promoted effector and memory-like T cell states, respectively, whereas anti-PD-1 did not markedly alter T cell differentiation, yet conferred the greatest survival benefit against metastatic tumors. Notably, anti-PD-1 induced epigenetic remodeling, which was detectable upon metastatic recall, consistent with the maintenance of a circulatory intermediate-exhausted T cell state. Thus, while effector and memory precursor-like T cells could be generated with IFN-β and agonistic anti-CD40, only the intermediate-exhausted T cell state driven by anti-PD-1 supported durable anti-tumor immunity. Dataset for preprint: doi.org/10.1101/2025.11.25.690601在癌症中，CD8+ T细胞应答以耗竭性T细胞（exhausted T cells）为主导，这类细胞可通过免疫检查点阻断疗法（immune checkpoint blockade therapy）重新激活，并能够抑制大型肿瘤生长。然而，目前尚不清楚哪种T细胞命运最能支持肿瘤消退或清除后，以及抗原负荷极低时期的长期免疫。这一问题在手术切除肿瘤后尤为关键，此时调节免疫系统或可预防肿瘤复发。为明确哪种T细胞命运可在术后及转移性肿瘤再攻击时提供持久保护，我们采用抗PD-1、IFN-β或激动性抗CD40（agonistic anti-CD40）调节T细胞致敏过程，并评估其对CD8+ T细胞分化及总生存期的影响。IFN-β与激动性抗CD40分别促进了效应性T细胞及记忆样T细胞状态的形成，而抗PD-1虽未显著改变T细胞分化，却在对抗转移性肿瘤时带来了最大的生存获益。值得注意的是，抗PD-1诱导了表观遗传重塑（epigenetic remodeling），该重塑在转移性肿瘤再次攻击时可被检测到，这与循环中间耗竭性T细胞状态的维持相一致。综上，尽管IFN-β与激动性抗CD40可诱导产生效应性T细胞及记忆前体样T细胞，但唯有抗PD-1驱动的中间耗竭性T细胞状态，能够支持持久的抗肿瘤免疫。本预印本数据集：doi.org/10.1101/2025.11.25.690601