Details

Autor(en) / Beteiligte

• Motz, Gregory T
• Santoro, Stephen P
• Wang, Li-Ping
• Garrabrant, Tom
• Lastra, Ricardo R
• Hagemann, Ian S
• Lal, Priti
• Feldman, Michael D
• Benencia, Fabian
• Coukos, George

Titel

Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors

Ist Teil von

• Nature medicine, 2014-06, Vol.20 (6), p.607-615

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Tumors use numerous mechanisms to escape detection and killing by the immune system. George Coukos and colleagues now report that cancer cells can also co-opt tumor-associated endothelial cells to prevent immune eradication. The researchers show that factors secreted by cancer cells induce increased expression of Fas ligand on the tumor endothelium, resulting in killing of CD8 + effector T cells and thereby facilitating immune escape and tumor growth. We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce CD8 + infiltration and a predominance of FoxP3 + T regulatory (T reg ) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E 2 (PGE 2 ) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8 + T cells but not T reg cells because of higher levels of c-FLIP expression in T reg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8 + over FoxP3 + T cells. Pharmacologic inhibition of VEGF and PGE 2 produced a marked increase in the influx of tumor-rejecting CD8 + over FoxP3 + T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors.