Immunotherapy of melanoma: A dichotomy in the requirement for IFN-gamma invaccine-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 challe nged the requirement for cytotoxicity mediated by either the perforin/granz yme or Fas/Fas ligand pathway in T cell-mediated tumor regression. Many rep orts, including ours, suggest that tumor-specific production of IFN-gamma i s 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 knock out (GKO) mice. The results show an interesting dichotomy in the requiremen t for IFN-gamma: Antitumor immunity induced by active-specific immunotherap y (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 mic e with established pulmonary metastases and induced long term antitumor imm unity and depigmentation of skin. Furthermore, in vivo neutralization of IF N-gamma by mAb treatment or adoptive transfer into IFN-gamma receptor knock out mice failed to block the therapeutic efficacy of effector T cells gener ated from wild-type or perforin knockout mice. Analysis of regressing metas tases revealed similar infiltrates of macrophages and granulocytes in both wild-type and GKO mice. These results indicate that in this adoptive immuno therapy model, neither a direct effect on the tumor nor an indirect effect of IFN-gamma through activation of myeloid or lymphoid cells is critical fo r therapeutic efficacy.