Reprogramming endothelial cells to empower cancer immunotherapy

Abstract

Cancer immunity is subject to spatiotemporal regulation by leukocyte interaction with the tumor microenvironment. Growing evidence suggests an emerging role for the vasculature in tumor immune evasion and immunotherapy resistance. Beyond the conventional functions of the tumor vasculature, such as providing oxygen and nutrients to support tumor progression, we propose multiplex mechanisms for vascular regulation of tumor immunity: The immunosuppressive vascular niche locoregionally educates circulation-derived immune cells by angiocrines, aberrant endothelial metabolism induces T cell exclusion and inactivation, and topologically and biochemically abnormal vascularity forms a pathophysiological barrier that hampers lymphocyte infiltration. We postulate that genetic and metabolic reprogramming of endothelial cells may rewire the immunosuppressive vascular microenvironment to overcome immunotherapy resistance, serving as a next-generation vascular targeting strategy for cancer treatment.

Keywords: CAR T cells; angiogenesis; cancer immunotherapy; endothelial cell metabolism; tumor microenvironment; vascular reprogramming.

Figure 1.. Mechanisms of vascular-mediated tumor immunosuppression.

Tumor vasculature drives immune suppression through immunosuppressive niche function and abnormal vascularity at metabolic and genetic levels. Endothelial cells (ECs) develop adaptive metabolic mechanisms to support their survival and proliferation in the hypoxic tumor microenvironment (TME), including heightened rates of glycolysis and serine biosynthesis. Tumor ECs (TECs) also undergo genetic alterations mediated through cell plasticity or induced by TME cues, including pro-angiogenic factors, hypoxia, and oxidative stress. Aberrant EC metabolism stimulates vessel sprouting, induces vascular abnormalities, and results in the production of immunosuppressive metabolites including lactate and 2-hydroxyglutarate (2-HG), contributing to immunosuppressive vascular niche function. The altered transcriptome in tumor ECs is characterized by dysfunctional expression of genes associated with cell proliferation, migration, adhesion, and extracellular matrix (ECM) production, leading to vascular abnormality that induces T cell exclusion and inactivation. Furthermore, the genetically altered TECs express immunosuppressive factors, including prostaglandin Interleukin 10 (IL-10), Interleukin 6 (IL-6), Transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF), and inhibitory ligands, including programmed death-ligand 1 and 2 (PD-L1/2) and Fas, restricting T cell activation directly, or inhibiting T cell activity indirectly through alternative macrophage polarization. The figure was generated using Adobe Illustrator.

Figure 2.. Rewiring tumor endothelial cells as a promising therapeutic strategy.

Metabolic reprogramming of tumor endothelial cells (ECs) may decrease the production of immunosuppressive metabolites and reduce metabolic competition in the tumor microenvironment (TME) while inhibiting vascular abnormalities, leading to increased T cell activity, persistence, and infiltration. Genetic reprogramming of tumor-associated ECs may downregulate the secretion of immunosuppressive cytokines in the vascular niche, increase EC expression of adhesion proteins, decrease EC expression of immune-inhibitory ligands, induce EC extracellular matrix (ECM) remodeling, and normalize aberrant tumor vasculature, resulting in enhanced T cell adhesion, survival, migration, and infiltration.