Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids

Akihiro Tokunaga, Daisuke Sugiyama, Yuka Maeda, Allison Betof Warner, Katherine S. Panageas, Sachiko Ito, Yosuke Togashi, Chika Sakai, Jedd D. Wolchok, Hiroyoshi Nishikawa

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2701-2713
Number of pages13
JournalJournal of Experimental Medicine
Volume216
Issue number12
DOIs
Publication statusPublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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