Fas expression by tumor stroma is required for cancer eradication

The contribution of molecules such as perforin, IFN-gamma (IFN-gamma), and particularly Fas ligand (FasL) by transferred CD8(+) effector T (T-E) cells to rejection of large, established tumors is incompletely understood. Efficient attack against large tumors carrying a surrogate tumor antigen (mimicking a "passenger" mutation) by T-E cells requires action of IFN gamma on tumor stroma cells to avoid selection of antigen-loss variants. Because "cancer-driving" antigens (CDAs) are rarely counter-selected, IFN gamma may be expected to be dispensable in elimination of cancers by targeting a CDA. Here, initial regression of large, established tumors required neither IFN gamma, FasL, nor perforin by transferred CD8(+) T-E cells targeting Simian Virus (SV) 40 large T as CDA. However, cytotoxic T-E cells lacking IFN gamma or FasL could not prevent relapse despite retention of the rejection antigen by the cancer cells. Complete tumor rejection required IFN gamma-regulated Fas by the tumor stroma. Therefore, T-E cells lacking IFN gamma or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down-regulated.