The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published 7 March 2005. doi:10.1084/jem.20041684
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 779-791
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ARTICLE

 Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors

Ping Yu1,2, Youjin Lee1,2, Wenhua Liu2, Thomas Krausz2, Anita Chong3, Hans Schreiber1,2, and Yang-Xin Fu1,2

1 The Committee on Immunology, University of Chicago, Chicago, IL 60637
2 Department of Pathology, University of Chicago, Chicago, IL 60637
3 Department of Surgery, University of Chicago, Chicago, IL 60637

CORRESPONDENCE Ping Yu: pingyu{at}uchicago.edu OR Yang-Xin Fu: yfu{at}uchicago.edu

Tumor environment can be critical for preventing the immunological destruction of antigenic tumors. We have observed a selective accumulation of CD4+CD25+ T cells inside tumors. In a murine fibrosarcoma Ld-expressing Ag104, these cells made up the majority of tumor-infiltrating lymphocytes at the late stage of tumor progression, and their depletion during the effector phase, rather than priming phase, successfully enhanced antitumor immunity. We show here that CD4+CD25+ T cells suppressed the proliferation and interferon-{gamma} production of CD8+ T cells in vivo at the local tumor site. Blockade of the effects of IL-10 and TGF-ß partially reversed the suppression imposed by the CD4+ cells. Furthermore, local depletion of CD4+ cells inside the tumor resulted in a change of cytokine milieu and led to the eradication of well-established highly aggressive tumors and the development of long-term antitumor memory. Therefore, CD4+CD25+ T cells maintained an environment in the tumor that concealed the immunogenicity of tumor cells to permit progressive growth of antigenic tumors. Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.

Abbreviations used: Ag104Ld, Ld-expressing Ag104; CBA, cytometric bead array kit; DLN, draining lymph nodes; TIL, tumor-infiltrating lymphocytes; TLR4, toll-like receptor 4.


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