TY - JOUR
T1 - Fc-dependent depletion of tumor-infiltrating regulatory t cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma
AU - Simpson, Tyler R.
AU - Li, Fubin
AU - Montalvo-Ortiz, Welby
AU - Sepulveda, Manuel A.
AU - Bergerhoff, Katharina
AU - Arce, Frederick
AU - Roddie, Claire
AU - Henry, Jake Y.
AU - Yagita, Hideo
AU - Wolchok, Jedd D.
AU - Peggs, Karl S.
AU - Ravetch, Jeffrey V.
AU - Allison, James P.
AU - Quezada, Sergio A.
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
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U2 - 10.1084/jem.20130579
DO - 10.1084/jem.20130579
M3 - Article
C2 - 23897981
AN - SCOPUS:84884271914
SN - 0022-1007
VL - 210
SP - 1695
EP - 1710
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -