TY - JOUR
T1 - Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids
AU - Tokunaga, Akihiro
AU - Sugiyama, Daisuke
AU - Maeda, Yuka
AU - Warner, Allison Betof
AU - Panageas, Katherine S.
AU - Ito, Sachiko
AU - Togashi, Yosuke
AU - Sakai, Chika
AU - Wolchok, Jedd D.
AU - Nishikawa, Hiroyoshi
N1 - Funding Information:
A. Tokunaga is an employee of Kyowa Kirin. Y. Togashi received honoraria and research grant from Ono Pharmaceutical Company and Bristol-Myers Squibb. J.D. Wolchok lists the following interests: consultant, Adaptive Biotech, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Astellas, Bei-gene, Bristol-Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Genentech, Imvaq, Kleo Pharma, MedImmune, Merck, Neon Therapuetics, Ono Pharmaceutical, Polaris Pharma, Poly-noma, Psioxus, Puretech, Recepta, Trienza, Sellas Life Sciences, Serametrix, Surface Oncology, and Syndax; research support: Bristol-Myers Squibb, Medimmune, Merck Pharmaceuticals, and Genentech; equity in Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene, and Trieza. H. Nishikawa received honoraria and grants from Ono Pharmaceutical, Bristol-Myers Squibb, and Chugai Pharmaceutical, and grants from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Astellas Pharmaceutical, Sysmex, and BD Japan outside of this study. The other authors declare no competing financial interests.
Funding Information:
We thank D. Ha, Y. Tada, M. Takemura, and K. Teshima for technical assistance and special animal care by the Division of Experimental Animals, Nagoya University Graduate School of Medicine. This study was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid for Scientific Research S grant no. 17H06162 to H. Nishikawa and Challenging Exploratory Research grant no. 16K15551 to H. Nishikawa), by the National Cancer Center Research and Development Fund (no. 28-A-7 and 31-A-7 to H. Nishikawa), and by the Naito Foundation. This study was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (no. P30 CA008748 to J.D. Wolchok). A.B. Warner is supported by a grant from the Conquer Cancer Foundation of American Society of Clinical Oncology. A. Tokunaga is an employee of Kyowa Kirin. Y. Togashi received honoraria and research grant from Ono Pharmaceutical Company and Bristol-Myers Squibb. J.D. Wolchok lists the following interests: consultant, Adaptive Biotech, Advaxis, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Astellas, Beigene, Bristol-Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Genentech, Imvaq, Kleo Pharma, MedImmune, Merck, Neon Therapuetics, Ono Pharmaceutical, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trienza, Sellas Life Sciences, Serametrix, Surface Oncology, and Syndax; research support: Bristol-Myers Squibb, Medimmune, Merck Pharmaceuticals, and Genentech; equity in Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene, and Trieza. H. Nishikawa received honoraria and grants from Ono Pharmaceutical, Bristol-Myers Squibb, and Chugai Pharmaceutical, and grants from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Astellas Pharmaceutical, Sysmex, and BD Japan outside of this study. The other authors declare no competing financial interests. Author contributions: J.D. Wolchok and H. Nishikawa designed the research; A. Tokunaga, D. Sugiyama, Y. Maeda, S. Ito, Y. Togashi, and C. Sakai performed experiments; A.B. Warner obtained clinical data; A. Tokunaga, D. Sugiyama, Y. Maeda, A.B. Warner, K.S. Panageas, J.D. Wolchok, and H. Nishikawa analyzed data; and A. Tokunaga, A.B. Warner, J.D. Wolchok, and H. Nishikawa wrote the paper.
Funding Information:
This study was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid for Scientific Research S grant no. 17H06162 to H. Nishikawa and Challenging Exploratory Research grant no. 16K15551 to H. Nishikawa), by the National Cancer Center Research and Development Fund (no. 28-A-7 and 31-A-7 to H. Nishikawa), and by the Naito Foundation. This study was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (no. P30 CA008748 to J.D. Wolchok). A.B. Warner is supported by a grant from the Conquer Cancer Foundation of American Society of Clinical Oncology.
Publisher Copyright:
© 2019 Tokunaga et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1084/jem.20190738
DO - 10.1084/jem.20190738
M3 - Article
C2 - 31537643
AN - SCOPUS:85075956675
VL - 216
SP - 2701
EP - 2713
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 12
ER -