Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.

中文翻译：

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免疫治疗后 CTLA-4 Ig 治疗可提高抗肿瘤功效


免疫检查点疗法 (ICT) 可改善癌症患者的总体生存率，但可能会导致心肌炎等免疫相关不良事件 (irAE)。细胞毒性 T 淋巴细胞相关抗原 4 免疫球蛋白融合蛋白 (CTLA-4 Ig) 是一种通过 CD28 抑制 T 细胞共刺激的抑制剂，可逆转动物模型中的 irAE。然而，人们担心 ICT 可能会损害抗肿瘤反应。在小鼠肿瘤模型中，我们在 ICT 的同时给予 CTLA-4 Ig 1) 或 ICT 完成后给予 2)。联合治疗降低了抗肿瘤疗效，而 ICT 后给药则提高了疗效，且不影响 CD8 T 细胞的频率和功能。反应的改善与所使用的 ICT 无关，无论是 CTLA-4 还是 PD-1 阻断。 CTLA-4 Ig 显着降低了 Tregs 的频率。由此产生的 CD8/Treg 比率增加可能是 ICT 和 CTLA-4 Ig 疗效增强的基础。这种矛盾的机制表明，CTLA-4 Ig 方案可降低 irAE 严重程度，但不会损害抗肿瘤功效。