Immunopotentiating role of IFN-gamma in early and late stages of type 1 CD8 effector cell-mediated tumor rejection.
Type 1 cytolytic CD8 effector T cells (Tc1) characteristically secrete IFN-gamma. Using an OVA-transfected B16 melanoma lung tumor model, we show that OVA Ag-specific Tc1 cells mediate a reduction in tumor growth that significantly prolongs survival in tumor-bearing mice. Transfer of Tc1 cells from OT-I mice crossed to IFN-gamma-KO mice showed that IFN-gamma-deficient Tc1 effector cells were less therapeutically effective than corresponding cells from wildtype mice. Therapeutic effects were dependent, in part, on effector cell-derived IFN-gamma, which not only induced elevated levels of lung-derived IP-10 and RANTES chemokine message in vivo, but also increased the local accumulation of activated host-derived CD4(+)/CD44(High), CD8(+)/CD44(High), and non-T-immune cell populations at the tumor site. Over time, the numbers of host-derived immune cells increased in the lung, which correlated with an elevated production of IP-10 and RANTES and a continued reduction in tumor burden. Conversely, donor Tc1 cell numbers markedly diminished at corresponding times, suggesting that prolonged therapeutic responses were due to the presence of host-derived antitumor mechanisms. Moreover, adoptive transfer of IFN-gamma-deficient Tc1 cells into tumor-bearing IFN-gamma-KO recipients showed that both recipient and donor-derived IFN-gamma play a significant role in Tc1-mediated responses and that Tc1 effector cell immunotherapy is predominantly mediated by IFN-gamma-dependent mechanisms.
Dobrzanski
M J
MJ
Trudeau Institute, Saranac Lake, New York 12983, USA.
Reome
J B
JB
Dutton
R W
RW
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018946:Chemokine CCL5 / Q000235:genetics / Q000502:physiology; D000939:Epitopes; D005260:Female; D007167:Immunotherapy; D018836:Inflammation Mediators / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology*; D008175:Lung Neoplasms / Q000517:prevention & control*; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D018946:Chemokine CCL5; D000939:Epitopes; D018836:Inflammation Mediators; D012333:RNA, Messenger; D007371:Interferon-gamma; D010047:Ovalbumin