期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 216, 期 12, 页码 2701-2713出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20190738
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17H06162, 16K15551]
- National Cancer Center Research and Development Fund [28-A-7, 31-A-7]
- Naito Foundation
- National Institutes of Health/National Cancer Institute Cancer Center Support Grant [P30 CA008748]
- Conquer Cancer Foundation of American Society of Clinical Oncology
- Grants-in-Aid for Scientific Research [16K15551] Funding Source: KAKEN
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.
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