Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma.
In vitro differentiated CD8(+) T cells have been the primary focus of immunotherapy of cancer with little focus on CD4(+) T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4(+) T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8(+), B, natural killer (NK), and NKT cells. Proper activation of CD4(+) T cells in vivo was important for tumor clearance, as naive tumor-specific CD4(+) T cells could not completely treat tumor in lymphopenic common gamma chain (gamma(c))-deficient hosts. gamma(c) signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4(+) T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4(+) T cells.
Program in Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Ying
Y
Xie
Akgül
A
Akpinarli
Charles
C
Maris
Edward L
EL
Hipkiss
Malcolm
M
Lane
Eun-Kyung M
EK
Kwon
Pawel
P
Muranski
Nicholas P
NP
Restifo
Paul Andrew
PA
Antony
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D006801:Humans; D016219:Immunotherapy, Adoptive; D007370:Interferon Type I / Q000276:immunology / Q000627:therapeutic use; D008545:Melanoma / Q000276:immunology* / Q000473:pathology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D011257:Pregnancy Proteins / Q000276:immunology / Q000627:therapeutic use
D015704:CD4 Antigens; D007370:Interferon Type I; D011257:Pregnancy Proteins; C020947:interferon tau