Production of interferon-gamma by tumor-sensitized T cells is essential for interleukin-12-induced complete tumor eradication.
BACKGROUND
Interferon-gamma (IFN-gamma) is essential for eradication of established large tumors by interleukin-12 (IL-12), but the critical source of IFN-gamma has not been defined. Adoptive transfer of T cells into T cell-deficient mice allows for evaluation of the role of T cells and T cell production of IFN-gamma in the antitumor immune response.


METHODS
Wild-type C57BL/6, IL-12 receptor-beta1 knockout (IL-12Rbeta1 KO), IFN-gamma knockout (IFN-gamma KO), and IFN-gamma receptor-alpha knockout (IFN-gammaRalpha KO) mice were immunized and used as donors for adoptive transfer. Transfer of either splenocytes or CD90(+) T cells was performed into recipient T cell receptor-beta knockout (TCRbeta KO) and IFN-gamma/TCRbeta double knockout mice bearing 14-day subcutaneous MCA207 tumors. Half of the mice were treated with IL-12, and cure rates were compared.


RESULTS
Transfer of either 1/4 immunized spleen equivalent or 10(7) immunized T cells into both TCRbeta KO and IFN-gamma/TCRbeta KO mice resulted in 80% to 100% cure when given with IL-12. However, transfer of 10(7) immunized T cells from IFN-gamma KO mice into TCRbeta KO mice was ineffective with or without IL-12. T cell response to IL-12, but not IFN-gamma, was required for tumor regression.


CONCLUSIONS
Production of IFN-gamma by IL-12-responsive tumor-sensitized T cells is both necessary and sufficient for complete tumor eradication induced by IL-12. T cells are the source, but not the target, of IFN-gamma during tumor regression.
Lee
Natalie C
NC
Department of Surgery, University of California, San Francisco, USA.
Tsung
Kangla
K
Norton
Jeffrey A
JA
D019264:Adoptive Transfer; D000818:Animals; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012513:Sarcoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D018664:Interleukin-12; D007371:Interferon-gamma