Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes.
We have investigated the mechanisms whereby adoptively transferred murine CD8+ lymphocytes mediate tumor regressions. Noncytolytic, CD8+ tumor-infiltrating lymphocytes (TIL) eradicated established lung tumors in irradiated mice. Many cytolytic and noncytolytic CD8+ TIL cultures specifically secreted interferon gamma (IFN-gamma) and tumor necrosis factor when stimulated with tumor cells in vitro. The effectiveness of TIL when adoptively transferred to mice bearing micrometastases correlated better with their ability to specifically secrete lymphokines than with their cytotoxicity in vitro. In 14 of 15 tests, therapeutically effective TIL specifically secreted IFN-gamma in vitro, whereas only 1 of 11 ineffective TIL specifically secreted IFN-gamma. In contrast, only 8 of 15 therapeutically effective TIL were cytolytic. Antibodies to TNF inhibited the effectiveness of two adoptively transferred TIL cultures. In five experiments, antibodies to IFN-gamma abrogated the ability of four different CD8+ TIL cultures to mediate tumor regressions, indicating that secretion of IFN-gamma is an essential part of the mechanism of action of TIL.
Barth
R J
RJ
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Mulé
J J
JJ
Spiess
P J
PJ
Rosenberg
S A
SA
D000818:Animals; D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D016827:CD8 Antigens; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology / Q000628:therapy*; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000276:immunology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D012513:Sarcoma, Experimental / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma