Immunopotentiating Role of IFN-γ 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-γ. 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-γ-KO mice showed that IFN-γ-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-γ, 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+/CD44High, CD8+/CD44High, 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-γ-deficient Tc1 cells into tumor-bearing IFN-γ-KO recipients showed that both recipient and donor-derived IFN-γ play a significant role in Tc1-mediated responses and that Tc1 effector cell immunotherapy is predominantly mediated by IFN-γ-dependent mechanisms.