Patients treated with immune checkpoint blockade (ICB) sometimes experience immune-related adverse events (irAEs), requiring immuno-suppressive drugs such as corticosteroids despite the possibility that immunosuppression may impair the antitumor effects of ICB. Here, we address the dilemma of using corticosteroids for the treatment of irAEs induced by ICB. ICB augments neoantigen-specific CD8⁺ T cell responses, resulting in tumor regression. In our model, simultaneous, but not late, administration of corticosteroids impaired antitumor responses with reduction of CD8⁺ T cell proliferation. Secondary challenge using tumors with/without the neoantigen showed selective progression in tumors lacking the neoantigen when corticosteroids were administered. Corticosteroids decreased low- but not high-affinity memory T cells by suppressing fatty acid metabolism essential for memory T cells. In a small cohort of human melanoma patients, overall survival was shorter after treatment with CTLA-4 blockade in patients who received early corticosteroids or had low tumor mutation burden. Together, low-affinity memory T cells are dominantly suppressed by corticosteroids, necessitating careful and thoughtful corticosteroid use.

接受免疫检查点封锁（ICB）治疗的患者有时会发生与免疫相关的不良事件（irAE），需要免疫抑制药物，例如皮质类固醇，尽管免疫抑制可能会损害ICB的抗肿瘤作用。在这里，我们解决了使用皮质类固醇治疗ICB诱发的irAEs的难题。ICB增强了新抗原特异性CD8 ⁺ T细胞反应，导致肿瘤消退。在我们的模型中，同时（但不晚）服用皮质类固醇会降低CD8 ⁺，从而降低抗肿瘤反应T细胞增殖。使用含/不含新抗原的肿瘤的二次攻击显示，在给予皮质类固醇激素后，缺乏新抗原的肿瘤选择性进展。皮质类固醇通过抑制记忆性T细胞必不可少的脂肪酸代谢，降低了低亲和力而不是高亲和力的记忆T细胞。在一小群人类黑色素瘤患者中，接受早期皮质类固醇治疗或肿瘤突变负担低的患者接受CTLA-4阻断治疗后，总生存期缩短。在一起，低亲和力记忆T细胞主要被皮质类固醇抑制，因此需要谨慎而周到地使用皮质类固醇。