VISTA Expression on Cancer-Associated Endothelium Selectively Prevents T-cell Extravasation

Sietse J. Luk*, Rouven Schoppmeyer, Marieke E. Ijsselsteijn, Antonios Somarakis, Ibtissam Acem, Dennis F.G. Remst, Daan T. Cox, Cornelis A.M. van Bergen, Inge Briaire-De Bruijn, Max L.B. Grönloh, Werner J. van der Meer, Lukas J.A.C. Hawinkels, Roman I. Koning, Erik Bos, Judith V.M.G. Bovée, Noel F.C.C. de Miranda, Karoly Szuhai, Jaap D. van Buul, J. H.Frederik Falkenburg, Mirjam H.M. Heemskerk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Cancers evade T-cell immunity by several mechanisms such as secretion of anti-inflammatory cytokines, down regulation of antigen presentation machinery, upregulation of immune checkpoint molecules, and exclusion of T cells from tumor tissues. The distribution and function of immune checkpoint molecules on tumor cells and tumor-infiltrating leukocytes is well established, but less is known about their impact on intratumoral endothelial cells. Here, we demonstrated that V-domain Ig suppressor of T-cell activation (VISTA), a PD-L1 homolog, was highly expressed on endothelial cells in synovial sarcoma, subsets of different carcinomas, and immune-privileged tissues. We created an ex vivo model of the human vasculature and demonstrated that expression of VISTA on endothelial cells selectively prevented T-cell transmigration over endothelial layers under physiologic flow conditions, whereas it does not affect migration of other immune cell types. Furthermore, endothelial VISTA correlated with reduced infiltration of T cells and poor prognosis in metastatic synovial sarcoma. In endothelial cells, we detected VISTA on the plasma membrane and in recycling endosomes, and its expression was upregulated by cancer cell–secreted factors in a VEGF-A–dependent manner. Our study reveals that endothelial VISTA is upregulated by cancer-secreted factors and that it regulates T-cell accessibility to cancer and healthy tissues. This newly identified mechanism should be considered when using immunotherapeutic approaches aimed at unleashing T cell–mediated cancer immunity.

Original languageEnglish
Pages (from-to)1480-1492
Number of pages13
JournalCancer Immunology Research
Volume11
Issue number11
DOIs
Publication statusPublished - 1 Nov 2023

Bibliographical note

Publisher Copyright:
©2023 American Association for Cancer Research.

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