Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts

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Title Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts
Author Quezada, Sergio A.; Simpson, Tyler R.; Peggs, Karl S.; Merghoub, Taha; Vider, Jelena; Fan, Xiaozhou; Blasberg, Ronald; Yagita, Hideo; Muranski, Pawel; Antony, Paul A.; Restifo, Nicholas P.; Allison, James P.
Journal Name Journal of Experimental Medicine
Year Published 2010
Place of publication United States
Publisher The Rockefeller University Press
Abstract Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1084/jem.20091918
Copyright Statement Copyright 2010 Rockefeller University Press. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
Volume 207
Issue Number 3
Page from 637
Page to 650
ISSN 0022-1007
Date Accessioned 2012-04-10
Language en_US
Research Centre Heart Foundation Research Centre; Molecular Basis of Disease
Faculty Griffith Health Faculty
Subject Cancer Therapy (excl Chemotherapy and Radiation Therapy)
URI http://hdl.handle.net/10072/44691
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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