Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer. Int J Mol Sci 2024 Sep 12;25(18)
Date
09/28/2024Pubmed ID
39337337Pubmed Central ID
PMC11432579DOI
10.3390/ijms25189853Scopus ID
2-s2.0-85205336576 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression-a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies.
Author List
Ghadrdoost Nakhchi B, Kosuru R, Chrzanowska MAuthor
Magdalena Chrzanowska PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Endothelial Cells
Endothelium, Vascular
Humans
Immune Tolerance
Mice
Neoplasms
Neovascularization, Pathologic
Signal Transduction
Tumor Microenvironment
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
rap GTP-Binding Proteins
