The Journal of Experimental Medicine
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Published online 26 August 2002 doi:10.1084/jem.20012142
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© Rockefeller University Press, 0022-1007/2002/9/619/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 5, September 2, 2002 619-628
Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma

Tomohide Tatsumi1, Lisa S. Kierstead1, Elena Ranieri1,4, Loreto Gesualdo4, Francesco P. Schena4, James H. Finke5, Ronald M. Bukowski5, Jan Mueller-Berghaus1, John M. Kirkwood2,6, William W. Kwok7 and Walter J. Storkus1,3,6

1 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
2 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
3 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
4 Department of Emergency and Organ Transplantation, Section of Nephrology, University of Bari, Bari 70124, Italy
5 Cleveland Clinic Foundation, Cleveland, OH 44195
6 University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261
7 Department of Immunology, Virginia Mason Research Center, Seattle, WA 98101

Address correspondence to Walter J. Storkus, Professor of Surgery, Molecular Genetics and Biochemistry, and Pathology, W1555 Biomedical Sciences Tower, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261. Phone: 412-624-6453; Fax: 412-624-1172; E-mail: storkuswj{at}msx.upmc.edu

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRß1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-{gamma} and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-ß1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit.

Key Words: melanoma • renal cell carcinoma • helper T lymphocyte • MAGE-6 • epitope


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