Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids
Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids
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DOI：
10.1084/jem.20190738
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发表时间：
2019-12-01
影响因子：
15.3
通讯作者：
Nishikawa, Hiroyoshi
中科院分区：
文献类型：
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作者：
Tokunaga, Akihiro;Sugiyama, Daisuke;Nishikawa, Hiroyoshi
接受免疫检查点阻断（ICB）治疗的患者有时会发生免疫相关不良事件（irAE），需要使用免疫抑制药物（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诱导的irAE的困境。ICB增强新抗原特异性CD 8（+）T细胞应答，导致肿瘤消退。在我们的模型中，同时（而不是晚些时候）给予皮质类固醇损害了抗肿瘤反应，降低了CD 8（+）T细胞增殖。使用有/无新抗原的肿瘤进行的二次激发显示，当给予皮质类固醇时，缺乏新抗原的肿瘤选择性进展。皮质类固醇通过抑制记忆T细胞所必需的脂肪酸代谢来降低低亲和力但不高亲和力的记忆T细胞。在一小群人黑色素瘤患者中，早期接受皮质类固醇或肿瘤突变负荷低的患者接受CTLA-4阻断治疗后的总生存期较短。总之，低亲和力记忆T细胞主要受到皮质类固醇的抑制，需要谨慎和周到的皮质类固醇使用。
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.