Figure 1.

Modulating vascular-immune interactions in solid tumors via TLS and HEV formation. (A) In solid tumors, vascular-immune interactions promote immunosuppression and neovascularization to allow the growth of cancer cells. Continuous angiogenic sprouting of ECs leads to an abnormal, less mature tumor vasculature with poor pericyte coverage leading to leakiness, dysfunctional blood flow and increased interstitial pressure which in turn promotes hypoxia and necrosis. Importantly, tumor blood vessels convey immunosuppressive signals that inhibit CD4⁺ and CD8⁺ lymphocyte infiltration, DC maturation and activate immunosuppressive regulatory T-cells (Tregs). Finally, innate immune cells, including TAMs and neutrophils, also suppress immunosurveillance and promote vascular remodeling. (B) Tumoral TLS and HEV induction promote anti-tumor immunity. In an immune-stimulatory setting, the tumor vasculature becomes transiently normalized with increased pericyte coverage, thus re-establishing blood flow and perfusion and reducing hypoxic and necrotic areas of the tumor. Due to the enhanced functionality, vessels are angiostatic and more prone to recruit immune cells which can lead to the formation of HEVs. Subsequently, HEV-containing TLSs form, with immune cell centers composed of CD4+ and CD8+ T, B lymphocytes, and mature DCs that promote an anti-tumor immune response. Tregs, TAMs, and neutrophils are less abundant, thus no longer exerting an immunosuppressive function. Altogether, re-awakening and boosting the immune system via TLS and HEV formation leads to reduced tumor cell growth and is ultimately beneficial for cancer progression. ECM, extra-cellular matrix; EC, endothelial cell; TLS, tertiary-lymphoid structure; HEV, high endothelial venule; HEC, high endothelial cell; iDC, immature dendritic cell; mDC, mature dendritic cell NK, Natural Killer cell; TAM, tumor-associated macrophage; RBC, red blood cell.