Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts.
Adoptive transfer of large numbers of tumor-reactive CD8(+) cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8(+) CTLs, with much less emphasis on the role and contribution of CD4(+) T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4(+) T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4(+) T cells developed cytotoxic activity, and tumor rejection was dependent on class II-restricted recognition of tumors by tumor-reactive CD4(+) T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4(+) T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4(+) T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4(+) cells in vivo over current protocols favoring in vitro expansion and differentiation.
Ludwig Center for Cancer Immunotherapy, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Sergio A
SA
Quezada
Tyler R
TR
Simpson
Karl S
KS
Peggs
Taha
T
Merghoub
Jelena
J
Vider
Xiaozhou
X
Fan
Ronald
R
Blasberg
Hideo
H
Yagita
Pawel
P
Muranski
Paul A
PA
Antony
Nicholas P
NP
Restifo
James P
JP
Allison
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002455:Cell Division; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000276:immunology* / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014357:Trypsin / Q000235:genetics
D007371:Interferon-gamma; C489303:PRSS1 protein, human; D014357:Trypsin