Fc-dependent depletion of tumor-infiltrating regulatory t cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma

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Abstract

Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fc? receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a contextdependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies © 2013 Simpson et al.

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Simpson, T. R., Li, F., Montalvo-Ortiz, W., Sepulveda, M. A., Bergerhoff, K., Arce, F., … Quezada, S. A. (2013). Fc-dependent depletion of tumor-infiltrating regulatory t cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Journal of Experimental Medicine, 210(9), 1695–1710. https://doi.org/10.1084/jem.20130579

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