Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors

By Gregory T. Motz, Stephen P. Santoro, Li-ping Wang, T. Garrabrant, R. Lastra, Ian Hagemann, P. Lal, M. Feldman, F. Benencia, George Coukos. Nature Medicine, 2014

941 citations recorded by the source corpus.

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 (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8+ T cells but not Treg cells because of higher levels of c-FLIP expression in Treg 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 PGE2 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.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/ac9f302c52190482b50ebe138f14b775a8ca7127

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Citations in the corpus

Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “The tumor vasculature plays a key role in T-cell homing into tumors (Buckanovich et al., 2008; Motz et al., 2014).”
Neoantigens: promising targets for cancer therapy (2023, background): “Moreover, most cancer cells and intratumoral vascular endothelial cells express high levels of Fas ligand (FasL), which is related to a lack of CD8 infiltration.(374,512) Fas-FasL interactions in the TME during ACT may lead to T cell death.”
Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma (2016, positive): “FasL expression by immunohistochemistry (IHC) has been described as a potential barrier to immune cells in several cancers, including renal cell carcinoma (RCC) 13 .”
ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA (2014, positive): “As stated earlier, the abnormal microenvironment of tumors helps tumors evade the immune response through multiple mechanisms, including impairment of lymphocyte infiltration, upregulation of immune checkpoint protein expression via hypoxia, recruitment of Tregs, and establishment of an immunosuppre”
Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “studied FasL expression in tissue microarrays (TMAs) of human breast, renal, bladder, colon, prostate and ovarian adenocarcinomas and control TMAs derived from healthy tissues.(128) Normal vasculature tissue did not express FasL, whereas the blood vessels of primary and metastatic tumors did, which ”
IFN-&ggr;–related mRNA profile predicts clinical response to PD-1 blockade (2017, background): “, WNT/β-catenin pathway activation) (25), failure of T cell priming (amenable to reversal by tumor-specific vaccines, oncolytic viruses, or adoptive T cell therapy), or the activity of other cells in the tumor microenvironment, such as stromal cells (26) or vascular endothelial cells (27).”