GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells

Although treatment with the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21-producing follicul...

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Bibliographic Details
Published in:Cancer immunology research 2020-05, Vol.8 (5), p.698-709
Main Authors: Koh, Choong-Hyun, Kim, Il-Kyu, Shin, Kwang-Soo, Jeon, Insu, Song, Boyeong, Lee, Jeong-Mi, Bae, Eun-Ah, Seo, Hyungseok, Kang, Tae-Seung, Kim, Byung-Seok, Chung, Yeonseok, Kang, Chang-Yuil
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
Cell Line, Tumor
Cytokines - metabolism
Disease Models, Animal
Female
Glucocorticoid-Induced TNFR-Related Protein - agonists
Glucocorticoid-Induced TNFR-Related Protein - immunology
Interleukins - immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Neoplasms - drug therapy
Neoplasms - immunology
Neoplasms - metabolism
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Helper-Inducer - immunology
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Summary:Although treatment with the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21-producing follicular helper T (Tfh) cells play a crucial role in DTA-1-induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-19-0748