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Endothelial Rap1B mediates T-cell exclusion to promote tumor growth: a novel mechanism underlying vascular immunosuppression

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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 (Rap1BiΔEC) 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 Rap1BiΔEC 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 Rap1BiΔEC 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.

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Funding

This work was funded by NIH grant R01HL111582 (M.C.). W.C. is supported by American Cancer Society Research Scholar Grant. RK is supported by the Director’s Fellowship Award at the Versiti Blood Research Institute, Wisconsin.

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Authors and Affiliations

  1. Versiti Blood Research Institute, Milwaukee, WI, 53201-2178, USA

    Guru Prasad Sharma, Ramoji Kosuru, Sribalaji Lakshmikanthan, Shikan Zheng, Yao Chen, Robert Burns, Gang Xin, Weiguo Cui & Magdalena Chrzanowska

  2. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA

    Yao Chen & Weiguo Cui

  3. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Magdalena Chrzanowska

  4. Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Magdalena Chrzanowska

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  1. Guru Prasad Sharma
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  2. Ramoji Kosuru
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Contributions

M.C. designed the research, provided funding, analyzed data, and wrote the manuscript; G.P.S. and R.K. performed the experiments, analyzed data, prepared figures, drafted the manuscript; S.L. generated data; S.Z. and R.B analyzed data; Y.C. and G.X. designed the experiments; W.C. designed the experiments and provided funding. All authors reviewed the manuscript.

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Correspondence to Magdalena Chrzanowska.

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Sharma, G.P., Kosuru, R., Lakshmikanthan, S. et al. Endothelial Rap1B mediates T-cell exclusion to promote tumor growth: a novel mechanism underlying vascular immunosuppression. Angiogenesis 26, 265–278 (2023). https://doi.org/10.1007/s10456-022-09862-5

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