Abstract
Fas ligand (FASL)-expressing tumor vasculature restricts CD8+ T-cell infiltration into tumors.
Major finding: Fas ligand (FASL)-expressing tumor vasculature restricts CD8+ T-cell infiltration into tumors.
Mechanism: Tumor-derived VEGF, IL10, and PGE2 induce endothelial FASL expression to kill effector T cells.
Impact: Reduction of endothelial FASL through VEGF and PGE2 inhibition may restore antitumor immune responses.
The tumor endothelium integrates angiogenic and immunosuppressive signals to limit infiltration of T cells into tumors and promote immune evasion. Given that FAS ligand (FASL) is a known mediator of T- cell apoptosis that has been shown to be expressed on the tumor endothelium, Motz and colleagues evaluated the role of FASL in regulation of the tumor endothelial barrier. FASL was highly expressed in tumor blood vessels across six types of cancers compared with normal vasculature and most tumor cells. FASL-expressing endothelial cells were capable of killing effector T cells, but regulatory T cells were resistant to FASL, suggesting that FASL suppresses antitumor immune responses by shifting the balance between effector T cells and Tregs in tumors. Consistent with this finding, endothelial FASL expression was associated with a lower number of infiltrating CD8+ T cells across several human solid tumor types. The authors screened tumor-derived soluble factors for the ability to upregulate FASL in endothelial cells and found that IL10, prostaglandin E2 (PGE2), and VEGF cooperated to induce FASL expression in human microvascular endothelia. Combined pharmacologic blockade of PGE2 production with acetylsalicylic acid (aspirin) and VEGFA inhibition with a VEGF-neutralizing antibody effectively abrogated endothelial FASL induction by ovarian cancer cell supernatants and suppressed both FASL expression on tumor endothelial cells and tumor growth in multiple xenograft mouse models in a CD8+ T-cell–dependent manner. Additionally, blockade of endothelial FASL signaling enhanced the efficacy of adoptive transfer of antitumor T cells from syngeneic mice and prolonged survival. Therefore, in addition to highlighting a central role of endothelial FASL expression in tumor immune tolerance, these findings suggest that combined strategies that target angiogenic and immunosuppressive mechanisms will be needed to effectively inhibit tumor progression.