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

Abstract

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.

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Figure 1: Expression of FasL on the human tumor endothelium.
Figure 2: Endothelial FasL kills T cells.
Figure 3: Expression of FasL by endothelial cells is regulated by the tumor microenvironment.
Figure 4: Proangiogenic growth factors induce FasL expression in vivo.
Figure 5: Endothelial FasL expression limits anti-tumor immunity by suppressing CD8 T cell infiltration in mice.
Figure 6: FasL blockade enhances T cell infiltration.

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Acknowledgements

This project was supported by US National Institutes of Health Transformative R01 CA156695 (G.C.), US National Cancer Institute (NCI) training grant T32 CA009140 (G.T.M.), a grant by the Ovarian Cancer Research Fund (G.T.M.) and NCI training grant R25 CA101871 (S.P.S.). We thank S. Nagata (Kyoto University) for the FasL expression plasmids and C. June (University of Pennsylvania) for the lentivirus expression vector. We also thank D. Powell and A. Facciabene for thoughtful discussion.

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G.T.M. designed experiments, generated data, performed analysis and wrote the manuscript. S.P.S., T.G. and F.B. generated data. L.-P.W. performed the immunohistochemical staining. R.R.L., I.S.H., P.L. and M.D.F. provided pathology support and scoring assistance. G.C. conceived the project, performed analysis and cowrote the manuscript.

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Correspondence to George Coukos.

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The authors declare no competing financial interests.

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Motz, G., Santoro, S., Wang, LP. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20, 607–615 (2014). https://doi.org/10.1038/nm.3541

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