Faculty Collaboration Database

Endothelial Rap1B mediates T-cell exclusion to promote tumor growth: a novel mechanism underlying vascular immunosuppression. Angiogenesis 2023 May;26(2):265-278

Date

11/21/2022

Pubmed ID

36403190

DOI

10.1007/s10456-022-09862-5

Scopus ID

2-s2.0-85142245350 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor A(VEGF-A) modulates tumor EC response to exclude T-cells are not well understood. Here, we demonstrate that EC-specific deletion of small GTPase Rap1B, previously implicated in normal angiogenesis, restricts tumor growth in endothelial-specific Rap1B-knockout (Rap1B^iΔEC) mice. EC-specific Rap1B deletion inhibits angiogenesis, but also leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8⁺ T-cells. Depletion of CD8⁺ T-cells restored tumor growth in Rap1B^iΔEC mice. Mechanistically, global transcriptome and functional analyses indicated upregulation of signaling by a tumor cytokine, TNF-α, and increased NF-κB transcription in Rap1B-deficient ECs. Rap1B-deficiency led to elevated proinflammatory chemokine and Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was elevated in tumor ECs from Rap1B^iΔEC mice. Significantly, Rap1B deletion prevented VEGF-A-induced immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-A-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-A-dependent desensitization of EC to proinflammatory stimuli. Significantly, they identify EC Rap1B as a potential novel vascular target in cancer immunotherapy.

Author List

Sharma GP, Kosuru R, Lakshmikanthan S, Zheng S, Chen Y, Burns R, Xin G, Cui W, Chrzanowska M

Authors

Magdalena Chrzanowska PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Guru Prasad Sharma Research Scientist I in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CD8-Positive T-Lymphocytes
Endothelial Cells
Mice
NF-kappa B
Neoplasms
Tumor Microenvironment
Tumor Necrosis Factor-alpha
Vascular Endothelial Growth Factor A
rap GTP-Binding Proteins