—a type of treatment that harnesses the body’s own immune system to recognize, attack, and destroy cancer cells—has shown remarkable success in treating various types of cancer in recent years. However, to advance development of these therapies further, a better understanding of the cell-cell interactions within the tumor microenvironment (TME) is needed. One key cellular component of the TME is the network of blood vessels, whose main function is to supply the tumor with nutrients and help it grow. These blood vessels, formed by endothelial cells (ECs), however, also serve as an important avenue for the transport of immune cells, including T-killer cells, to the tumor.
on these TME interactions, revealing that a protein called Rap1B in ECs plays a major role in how blood vessels form and function, and how ECs impact access of immune cells to the tumor. These novel findings, published in Angiogenesis, may open the door to new therapeutic targets that enhance the body’s immune response against tumors.
“We discovered that the absence of Rap1B in ECs suppressed angiogenesis (the process by which new blood vessels are formed from existing ones), altering the TME, increasing recruitment and activity of tumor-killing CD8+ T-cells, and suppressing tumor growth,” said first author Guru Prasad Sharma, PhD, 果冻影院 postdoctoral fellow of radiation biology. “Mechanistically, Rap1B controls interactions between ECs and immune cells by restraining proinflammatory responses and chemokine expression, and diminishing leukocyte recruitment to the tumor. Rap1B is also essential for mediating Vascular Endothelial Growth Factor A (VEGF-A)-induced immunosuppressive signaling in ECs, providing insights into a novel mechanism for VEGF-A-dependent modulation of proinflammatory stimuli.”
Dr. Sharma said these findings advance our understanding of Rap1B’s role in endothelial cell biology, demonstrating that it can be used as a potential therapeutic target to counteract vascular immunosuppression in cancer immunotherapy and improve treatment outcomes.
During the study, investigators used “genetic knockout” approaches to remove Rap1B from blood vessels of mice with melanoma tumors. They discovered that depleting the protein in ECs of mice blocked VEGF-A signaling, stopped angiogenesis, and led to an altered TME with increased number of CD8+ T-cells having higher cancer-fighting activity. Dr. Sharma said these new insights may help drive development of combination therapies that target both immunosuppressive pathways and angiogenesis, potentially enhancing the effectiveness of cancer immunotherapy and anti-angiogenic strategies.
“These findings could guide the identification of biomarkers for patient stratification, inform mechanistic investigations into tumor-immune interactions, and inspire the exploration of new therapeutic targets focused on disrupting the immunosuppressive effects of ECs,” he said.
Dr. Sharma thanks the research team for its guidance and collaboration on this important project, which was supported by NIH grant R01HL111582 awarded to , associate professor, Pharmacology and Toxicology, corresponding author of the study and Dr. Sharma’s mentor.