Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 6, Pages 2276-2281Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1218295110
Keywords
T-cell therapy; immune escape
Categories
Funding
- Deutsche Forschungsgemeinschaft [Sonderforschungsbereich TR36]
- Alliance Program of the Helmholtz-Gemeinschaft Deutscher Forschungszentren [HA-202]
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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.
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