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| 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 |
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| Author(s): Tatsumi T, Kierstead LS, Ranieri E, Gesualdo L, Schena FP, Finke JH, Bukowski RM, Mueller-Berghaus J, Kirkwood JM, Kwok WW, Storkus WJ |
| Source: JOURNAL OF EXPERIMENTAL MEDICINE Volume: 196 Issue: 5 Pages: 619-628 Published: SEP 2 2002 |
| Times Cited: 115 References: 49 |
| Abstract: 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)-DRbeta1*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)-beta1 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Storkus, WJ (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, W1555 Biomed Sci Tower,200 Lothrop St, Pittsburgh, PA 15261 USA |
Addresses:
1. Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15261 USA
2. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA
3. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA
4. Univ Bari, Dept Emergency & Organ Transplantat, Nephrol Sect, I-70124 Bari, Italy
5. Cleveland Clin Fdn, Cleveland, OH 44195 USA
6. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15261 USA
7. Virginia Mason Res Ctr, Dept Immunol, Seattle, WA 98101 USA |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA |
| Subject Category: Immunology; Medicine, Research & Experimental |
| IDS Number: 593HJ |
| ISSN: 0022-1007 |
| DOI: 10.1084/jem.20012142 |
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