Tumor rejection by local interferon gamma induction in established tumors is associated with blood vessel destruction and necrosis

It has been shown that injecting a suspension of IFN-gamma-secreting tumor cells results in their rejection. This effect has been attributed to IFN-gamma preventing tumor stroma formation but not to a direct effect on the cancer cells. However, it is not known, which influence IFN-gamma has on tumors with an established stroma. To address this question, the plasmacytoma cell line J558L was transduced with a vector allowing doxycycline-inducible IFN-gamma gene expression. After the injection of the tumor cells into mice, IFN-gamma was induced at different time points. Tumors did not grow when inducing IFN-gamma immediately after tumor cell inoculation, while approximately half of the tumors were rejected when IFN-gamma was induced in early established tumors within 2 weeks. Induction of IFN-gamma 2-3 weeks after tumor cell inoculation was less efficient (0-17% rejection). IFN-gamma induction in established tumors led to a reduction of CD146(+) endothelial cells and massive necrosis. Together, we show that vascularized tumors can be rejected by local IFN-gamma expression, but that rejection of established tumors was less efficient over time. This suggests that transplanted tumors became less susceptible to local IFN-gamma treatment the better they are established.