Local secretion of IFN-gamma induces an antitumor response: Comparison between T cells plus IL-2 and IFN-gamma transfected tumor cells

Previously we described that the adoptive transfer of tumor-infiltrating ly mphocytes (TIL) + interleukin-2 (IL-2) leads to eradication of established methyl cholanthrene (MCA)-105 fibrosarcoma pulmonary metastases in a congen ic murine model. The in vivo efficacy of TIL was associated with their abil ity to secrets interferon-gamma (IFN-gamma), and to a lesser extent granulo cyte-macrophage colony-stimulating factor. The local secretion of these cyt okines resulted in recruitment of naive host immune cells to the tumor and eventually in a successful host antitumor immune response. In the present s tudy, to further evaluate the role of IFN-gamma in the induction of a host antitumor immune response, we compared the treatment efficacy of adoptively transferred T cells and IFN-gamma gene transfected tumor cells (MCA-105/IF N-gamma) as delivery systems of IFN-gamma. Treatment with TIL-IL-2 or irrad iated MCA-105/IFN-gamma induced a similar reduction in pulmonary metastases of MCA-105 tumor. In contrast, irradiated wild-type MCA-105 or TIL from IF N-gamma gene knockout mice did not cause tumor eradication. MCA-105 tumor-b earing mice treated with MCA-205/IFN-gamma showed a partial reduction in th e number of pulmonary metastases. Histologically, lungs of successfully tre ated mice showed that initially activated macrophages expressing inducible nitric oxide synthase (iNOS) and dendritic cells infiltrated the tumor bed. Subsequently, CD4(+) and CD8(+) T cells infiltrated tumors. The therapeuti c efficacy of IFN-gamma transfected tumor cells was eliminated when either CD4(+) T cells or CD8(+) T cells were depleted. These results suggest that local secretion of IFN-gamma induces a tumor-specific host antitumor immune response mediated through activated macrophages, dendritic cells, and tumo r-specific T cells. This may be a common component of successful immunother apy.