Immunotherapy of melanoma: a dichotomy in the requirement for IFN-gamma in vaccine-induced antitumor immunity versus adoptive immunotherapy.
The mechanism by which tumors are rejected following the adoptive transfer of tumor-specific T cells is not well characterized. Recent work has challenged the requirement for cytotoxicity mediated by either the perforin/granzyme or Fas/Fas ligand pathway in T cell-mediated tumor regression. Many reports, including ours, suggest that tumor-specific production of IFN-gamma is critical for T cell-mediated tumor regression. However, in most of these studies the evidence to support the role for IFN-gamma is only indirect. We have directly examined the requirement for IFN-gamma using IFN-gamma knockout (GKO) mice. The results show an interesting dichotomy in the requirement for IFN-gamma: Antitumor immunity induced by active-specific immunotherapy (vaccination) required IFN-gamma, whereas adoptive immunotherapy did not. In GKO mice vaccination with the GM-CSF gene-modified B16BL6-D5 tumor (D5-G6) failed to induce protective immunity against parental D5 tumor. However, adoptive transfer of effector T cells from GKO mice cured 100% of GKO mice with established pulmonary metastases and induced long term antitumor immunity and depigmentation of skin. Furthermore, in vivo neutralization of IFN-gamma by mAb treatment or adoptive transfer into IFN-gamma receptor knockout mice failed to block the therapeutic efficacy of effector T cells generated from wild-type or perforin knockout mice. Analysis of regressing metastases revealed similar infiltrates of macrophages and granulocytes in both wild-type and GKO mice. These results indicate that in this adoptive immunotherapy model, neither a direct effect on the tumor nor an indirect effect of IFN-gamma through activation of myeloid or lymphoid cells is critical for therapeutic efficacy.
Winter
H
H
Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, OR 97213, USA.
Hu
H M
HM
McClain
K
K
Urba
W J
WJ
Fox
B A
BA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014820:Vitiligo / Q000235:genetics / Q000276:immunology
D019496:Cancer Vaccines; D016207:Cytokines; D007106:Immune Sera; D007371:Interferon-gamma