Selective inhibition of low-affinity memory CD8(+) T cells by corticosteroids
Open accessAbstract
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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In a mouse model, early CS treatment reduces antitumor activity of anti-PD-1 and anti-CTLA-4 monoclonal antibody in a dose-dependent fashion.
“Recently, it was reported in a mouse model that early CS treatment reduces antitumor activity of anti-PD-1 and anti-CTLA-4 monoclonal antibody (mAb) in a dose-dependent fashion.41”
From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [41]
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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
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-09-19
- Volume
- 216
- Issue
- 12
- Pages
- 2701-2713
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6888983
- 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
- hybrid
- doi.org
- Licence
- 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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