Cited by 124Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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

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Tokunaga, Akihiro, Sugiyama, Daisuke, Maeda, Yuka, Warner, Allison Betof, Panageas, Katherine S., Ito, Sachiko, Togashi, Yosuke, Sakai, Chika +2 more·2019·Journal of Experimental Medicine

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.

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Authors
Tokunaga, A., Sugiyama, D., Maeda, Y., Warner, A. B., Panageas, K. S., Ito, S., Togashi, Y., Sakai, C., Wolchok, J. D., & Nishikawa, H.
Affiliations
  • Kyowa Kirin (Japan) (JP)
  • Nagoya University (JP)
  • National Cancer Centre Japan (JP)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Nishikawa, Hiroyoshi
Venue
Journal of Experimental Medicine
Published
2019-09-19
Volume
216
Issue
12
Pages
2701-2713
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W2974799401
Cited by
124
References
42
Citations by year
2026: 14 · 2025: 11 · 2024: 23 · 2023: 19 · 2022: 16 · 2021: 21 · 2020: 17 · 2019: 2
FWCI
5.85
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (17H06162, 16K15551)
  • National Cancer Center Research and Development Fund (28-A-7, 31-A-7)
  • Naito Foundation
  • National Institutes of Health
  • National Cancer Institute (P30 CA008748)
  • Conquer Cancer Foundation
  • American Society of Clinical Oncology
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
corticosteroids, immune checkpoint blockade, immune-related adverse events, CD8+ T cells, memory T cells, fatty acid metabolism, CTLA-4 blockade, melanoma, tumor mutational burden, neoantigens, antitumor immunity, immunosuppression
MeSH terms
Adrenal Cortex Hormones, Animals, Cell Differentiation, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Immunologic Memory, Immunosuppressive Agents, Lymphocyte Activation, Melanoma, Mutation, Receptors, Steroid, Biomarkers, T-Lymphocyte Subsets, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Mice, CTLA-4 Antigen, Programmed Cell Death 1 Receptor

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