Targeting the vasculature to enhance anti-tumor immunity

University Of Virginia, Charlottesville VA

Investigators

Linked publications & trials

Abstract

SUMMARY Tumor blood vessels allow anti-tumor immune cells to enter the tumor microenvironment, but abnormalities in the tumor endothelium can impair immune cell entry, resulting in poor responses to immune checkpoint blockade (ICB). We recently found that genetic deletion of the epigenetic gene silencer DNA methyltransferase 1 (Dnmt1) in blood vessels primes the endothelium for cytokine stimulation, resulting in improved responses to ICB. This suggests that epigenetic reprogramming of the tumor vasculature could improve the efficacy of ICB and augment immune surveillance. We have now used melanoma cells with differing tumor mutation burden (TMB) and found that targeting Dnmt1 in the endothelium results in notable regression of TMBhi melanoma, increased CD4/CD8 memory T-cells and granzyme B+ effectors, increased dendritic cells and lymphatic vessels in tumor-draining lymph nodes, and a profound reduction in lung-metastatic burden following combinations of ICB. In this proposal, we aim to test three hypotheses: first, that genetic disruption of Dnmt1 in endothelial cells promotes long-term tumor control via dendritic cell trafficking to draining lymph nodes and recruitment of CD4+ T-cells; second, that targeting Dnmt1 in the vasculature of melanoma lung metastasis will reduce tumor burden and improve the efficacy of ICB; and third, that switching off endothelial Dnmt1 will promote the neogenesis of immune-permissive post-capillary venules and high endothelial venules in melanoma. This renewal proposal is led by Dr. Andrew Dudley, a Professor of Microbiology, Immunology, and Cancer Biology at UVA. Dr. Dudley is the MPI on the T32 Cancer Biology Training Grant at UVA, a member of the UVA Comprehensive Cancer Center, and he runs a research lab focused on tumor angiogenesis/tumor microenvironment. The proposal also includes Dr. Hong Zhu, a biostatistician and director of the Biostatistics Share Resource Center in the Department of Public Health Sciences, who will guide data analysis and statistics. Additionally, Dr. Melanie Rutkowski, an expert in using FACS to profile immune cells in tumors, and Dr. Craig Slingluff, a surgical oncologist with over 30 years of experience in cancer immunology and immunotherapy at UVA, are included on the proposal. Dr. Slingluff's research includes laboratory studies and clinical trials focused primarily on developing melanoma vaccines and combination immunotherapy. Taken together, a successful proposal will inform the development of vascular-directed therapies that can increase ICB efficacy against metastatic disease, identify creative approaches to lower the effective dose of ICB required for a favorable and sustained response, and further our understanding of how tumor vascular heterogeneity dictates anti-tumor immunity.