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 Blood, 9 April 2009, Vol. 113, No. 15, pp. 3494-3502.
Prepublished online as a Blood First Edition Paper on February 2, 2009; DOI 10.1182/blood-2008-08-175109.

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IMMUNOBIOLOGY

EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion

Alexandra Ziegler1,*, Regina Heidenreich1,*, Heidi Braumüller1,*, Hartwig Wolburg2, Susanne Weidemann1, Ralph Mocikat3, and Martin Röcken1

1 Department of Dermatology, University Medical Center and 2 Department of Pathology, Eberhard Karls University Tübingen, Tübingen; and 3 Institut für Molekulare Immunologie, Helmholtz-Zentrum München, München, Germany

Experimental tumor vaccination and adoptive T-cell therapies show that interferon-{gamma} (IFN-{gamma})–producing CD4+ T helper cells (Th1) can be highly effective in tumor prevention and therapy. Unexpectedly, first vaccine trials in humans revealed that tumor immune therapy may not only be protective, but, on the contrary, even promote tumor progression. Here, we analyzed T-cell immune responses to the epithelial cell adhesion molecule (EpCAM), one of the most common tumor-associated antigens (TAA) serving as immune target in colon cancer patients. Th-cell priming against EpCAM inevitably resulted in interleukin-4 (IL-4)–dominated Th2 responses, even under most stringent Th1-inducing conditions. These EpCAM-reactive Th2 cells rather promoted growth of EpCAM-expressing tumors. To analyze the role of IL-4 in tumor immune evasion, we generated EpCAM-reactive Th1 cells from IL-4.ko mice. These Th1 cells provided tumor-specific protection and established highly protective Th1 memory responses, even in naive BALB/c mice. Inhibition of tumor growth by Th1 cells resulted in intra-tumoral expression of cytokines of the IL-12 family and of IFN-{gamma}. Preventing activation-associated death of Th1 cells further increased intratumoral IFN-{gamma} expression and improved therapeutic efficacy. Thus, human TAA may promote tumor immune evasion by strongly favoring Th2 development.


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