Tumor-specific Th17-polarized cells eradicate large established melanoma.
CD4+ T cells can differentiate into multiple effector subsets, but the potential roles of these subsets in anti-tumor immunity have not been fully explored. Seeking to study the impact of CD4+ T cell polarization on tumor rejection in a model mimicking human disease, we generated a new MHC class II-restricted, T-cell receptor (TCR) transgenic mouse model in which CD4+ T cells recognize a novel epitope in tyrosinase-related protein 1 (TRP-1), an antigen expressed by normal melanocytes and B16 murine melanoma. Cells could be robustly polarized into Th0, Th1, and Th17 subtypes in vitro, as evidenced by cytokine, chemokine, and adhesion molecule profiles and by surface markers, suggesting the potential for differential effector function in vivo. Contrary to the current view that Th1 cells are most important in tumor rejection, we found that Th17-polarized cells better mediated destruction of advanced B16 melanoma. Their therapeutic effect was critically dependent on interferon-gamma (IFN-gamma) production, whereas depletion of interleukin (IL)-17A and IL-23 had little impact. Taken together, these data indicate that the appropriate in vitro polarization of effector CD4+ T cells is decisive for successful tumor eradication. This principle should be considered in designing clinical trials involving adoptive transfer-based immunotherapy of human malignancies.
Muranski
Pawel
P
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Mark O. Hatfield Clinical Research Center, Bethesda, MD 20892, USA. muranskp@mail.nih.gov
Boni
Andrea
A
Antony
Paul A
PA
Cassard
Lydie
L
Irvine
Kari R
KR
Kaiser
Andrew
A
Paulos
Chrystal M
CM
Palmer
Douglas C
DC
Touloukian
Christopher E
CE
Ptak
Krzysztof
K
Gattinoni
Luca
L
Wrzesinski
Claudia
C
Hinrichs
Christian S
CS
Kerstann
Keith W
KW
Feigenbaum
Lionel
L
Chan
Chi-Chao
CC
Restifo
Nicholas P
NP
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D007370:Interferon Type I / Q000276:immunology; D007371:Interferon-gamma; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011257:Pregnancy Proteins / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology
D007370:Interferon Type I; D011257:Pregnancy Proteins; C020947:interferon tau; D007371:Interferon-gamma