Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity

摘要

Tumor cells rapidly outgrow their blood supply, leading to hypoxia and acidosis in the tumor microenvironment (TME), which in turn promotes immunosuppressive mechanisms. Hypoxia stimulates HIF-1 and thereby upregulates VEGF. VEGF induces tumor angiogenesis, resulting in the malformed and malfunctional vasculature. Tumor endothelial cells exhibit immunosuppressive characteristics, such as PD-L1 expression, which enhance the exhaustion and apoptosis of T cells. Dendritic cell (DC) maturation is suppressed, resulting in interruption of T cell priming by impaired antigen presentation. In addition, TOX-mediated transcriptional reprogramming severely exhausts CD8+ T cells. Furthermore, tumor-associated macrophages (TAMs) polarize from an immunosupportive M1-like phenotype to an immunosuppressive M2-like phenotype. Regulatory T (Treg) cells also accumulate within the TME to promote tumor angiogenesis.