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

Abstract

Experimental tumor vaccination and adop-tive T-cell therapies show that interferon-γ (IFN-γ)-producing CD4+ T helper cells (Th1) can be highly effective in tumor prevention and therapy. Unexpectedly, first vaccine tri-als in humans revealed that tumor immune therapy may not only be protective, but, on the contrary, even promote tumor progres-sion. Here, we analyzed T-cell immune re-sponses to the epithelial cell adhesion mol-ecule (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 Thl-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-γ. Preventing activation- associated death of Th1 cells further in-creased intratumoral IFN-γ expression and improved therapeutic efficacy. Thus, human TAA may promote tumor immune evasion by strongly favoring Th2 development. © 2009 by The American Society of Hematology.