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Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy

Nature Medicine volume 14, pages 28–36 (2008)Cite this article

Abstract

In spite of their having sufficient immunogenicity, tumor vaccines remain largely ineffective. The mechanisms underlying this lack of efficacy are still unclear. Here we report a previously undescribed mechanism by which the tumor endothelium prevents T cell homing and hinders tumor immunotherapy. Transcriptional profiling of microdissected tumor endothelial cells from human ovarian cancers revealed genes associated with the absence or presence of tumor-infiltrating lymphocytes (TILs). Overexpression of the endothelin B receptor (ETBR) was associated with the absence of TILs and short patient survival time. The ETBR inhibitor BQ-788 increased T cell adhesion to human endothelium in vitro, an effect countered by intercellular adhesion molecule-1 (ICAM-1) blockade or treatment with NO donors. In mice, ETBR neutralization by BQ-788 increased T cell homing to tumors; this homing required ICAM-1 and enabled tumor response to otherwise ineffective immunotherapy in vivo without changes in systemic antitumor immune response. These findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.

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Figure 1: Distinct endothelial profiles detected in stage 3 human ovarian cancer with or without TILs by immuno-LCM coupled with gene expression profiling.
Figure 2: ETBR overexpression is associated with a paucity of intraepithelial TILs and poor survival in advanced-stage epithelial ovarian cancer.
Figure 3: ETBR blockade increases T cell adhesion to endothelium in vitro through effects on NO and ICAM-1.
Figure 4: ETBR blockade in vivo augments tumor immunotherapy without increasing systemic antitumor immune response.
Figure 5: ETBR blockade in vivo augments T cell homing to tumors after vaccination.
Figure 6: ETBR blockade in vivo augments T cell homing to tumors.

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Acknowledgements

pcDNA3.1-LLO-E7 vector was kindly provided by Y. Paterson (University of Pennsylvania). This work was supported by NIH grants R01-CA098951, P50-CA083638 Ovarian Cancer SPORE and R01-CA112162. A.F. was supported by the US National Ovarian Cancer Coalition. R.J.B. was supported by an NIH–National Institute of Child Health and Human Development grant (K12-HD43459 Career Development in Interdisciplinary Women's Health Research) and the Ovarian Cancer Research Fund. F.B. was supported by NIH grant D43-TW00671 and the Fogarty International Center. The Laser Capture Microdissection facility was supported by a generous grant from the Fannie Rippel Foundation.

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Author notes

  1. Ronald J Buckanovich

    Present address: Current address: Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.,

  2. Ronald J Buckanovich and Andrea Facciabene: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Research on Ovarian Cancer Early Detection and Cure, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Ronald J Buckanovich, Andrea Facciabene, Sarah Kim, Fabian Benencia, Dimitra Sasaroli, Klara Balint, Anne O'Brien-Jenkins, Phyllis A Gimotty & George Coukos

  2. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Ronald J Buckanovich

  3. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Fabian Benencia & George Coukos

  4. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Dimitra Sasaroli

  5. Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, 68100, Greece

    Phyllis A Gimotty

  6. Department of Obstetrics and Gynecology, University of Turin, Torino, 10126, Italy

    Dionysios Katsaros

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Correspondence to George Coukos.

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Buckanovich, R., Facciabene, A., Kim, S. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14, 28–36 (2008). https://doi.org/10.1038/nm1699

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