Anti-CTLA-4 antibodies in cancer immunotherapy: Selective depletion of intratumoral regulatory T cells or checkpoint blockade?
Date
2018Journal
Cell and BiosciencePublisher
BioMed Central Ltd.Type
Article
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Antibodies to human CTLA-4 have been shown to induce long-lasting protection against melanoma. It is assumed that these antibodies cause tumor rejection by blocking negative signaling from the B7-CTLA-4 interactions to enhance priming of naïveT cells in the lymphoid organs. Recently, we reported that anti-CTLA-4 antibody Ipilimumab effectively induces tumor rejection in vivo although it blocks neither B7 transendocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Using genetic model in which the anti-CTLA-4 antibodies are unable to engage more than 50% of CTLA-4, we demonstrated that saturating binding of CTLA-4 is not necessary for tumor rejection. Our results argue against B7-CTLA-4 blockade as the mechanism of action for the clinically effective Ipilimumab. Moreover, Ipilimumab induces tumor rejection even in the absence of de novo T cell priming in the lymphoid organs. Thus, our data are inconsistent with key provisions of the prevailing hypothesis on mechanism of action by anti-CTLA-4 antibodies. Furthermore, anti-CTLA-4 antibodies effectively induce depletion of regulatory T (Treg) cells in tumor microenvironment but not in the peripheral lymphoid organs, which is strictly dependent on Fc receptor on host cells. Based on these data and other recent publications on the subject, we propose that anti-human CTLA-4 antibodies induce tumor rejection by selective depletion of Tregs in the tumors rather than blockade of B7-CTLA-4 interaction in lymphoid organs. Copyright 2018 The Author(s).Sponsors
We would like to thank Juanjuan Su, Yan Zhang, Peng Zhang, Peiying Ye, Xu Wang, Wei Wu and other colleagues in our research team for discussions. This work is supported by NIH Grants (AI64350, CA171972 and AG036690) and a grant from OncoImmune, Inc.Keyword
B7-CTLA-4 interactionCancer immunotherapy
CTLA-4
Ipilimumab
Regulatory T cells
Tumor microenvironment
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https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045527893&doi=10.1186%2fs13578-018-0229-z&partnerID=40&md5=68f926e1ddc2a287c688e8058b9eacf8; http://hdl.handle.net/10713/9086ae974a485f413a2113503eed53cd6c53
10.1186/s13578-018-0229-z