Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell carcinoma or melanoma.
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.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Tomohide
T
Tatsumi
Lisa S
LS
Kierstead
Elena
E
Ranieri
Loreto
L
Gesualdo
Francesco P
FP
Schena
James H
JH
Finke
Ronald M
RM
Bukowski
Jan
J
Mueller-Berghaus
John M
JM
Kirkwood
William W
WW
Kwok
Walter J
WJ
Storkus
D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000939:Epitopes / Q000235:genetics; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D000951:Antigens, Neoplasm; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C095203:MAGEA6 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm