Immunomodulation by endothelial cells - partnering up with the immune system?

Abstract

Blood vessel endothelial cells (ECs) have long been known to modulate inflammation by regulating immune cell trafficking, activation status and function. However, whether the heterogeneous EC populations in various tissues and organs differ in their immunomodulatory capacity has received insufficient attention, certainly with regard to considering them for alternative immunotherapy. Recent single-cell studies have identified specific EC subtypes that express gene signatures indicative of phagocytosis or scavenging, antigen presentation and immune cell recruitment. Here we discuss emerging evidence suggesting a tissue-specific and vessel type-specific immunomodulatory role for distinct subtypes of ECs, here collectively referred to as 'immunomodulatory ECs' (IMECs). We propose that IMECs have more important functions in immunity than previously recognized, and suggest that these might be considered as targets for new immunotherapeutic approaches.

Fig. 1. Immunomodulation by ECs in lymph nodes and liver.

Known and putative insights into immunomodulation by endothelial cells (ECs) in lymph nodes and the liver. a | Lymph nodes contain high endothelial venules (HEVs), which express chemokines, adhesion molecules and other surface molecules (addressins) that facilitate the adhesion or recruitment of lymphocytes such as naive T cells (Tn cells). b | During inflammation (indicated by the red background), HEVs (upper panel) and venous ECs (bottom panel) in lymph nodes can recruit various immune cells, such as neutrophils, monocytes and effector T cells, in a selectin-dependent manner. c | In preclinical models of cancer, including breast cancer, melanoma that has metastasized to the lung and pancreatic cancer, anti-angiogenic therapy (AAT) or delivery of LIGHT protein, combined with immune checkpoint blockade (ICB), was found to increase HEV biogenesis, thereby promoting tumour immunity and immunotherapy^–. d | Interestingly, activated HEVs express additional immunomodulatory genes, which may impair dendritic cell (DC) activation (via reverse CD137–CD137L signalling), alter macrophage differentiation (via macrophage migration inhibitory factor (MIF)^,) or inhibit T cell activation (via thrombospondin 1 (TSP1)). e | Liver ECs with immunomodulatory properties (these are mostly liver sinusoidal ECs (LSECs)) facilitate tolerance to harmless gut flora-derived antigens through co-inhibition of CD8⁺ T cells via the checkpoint ligand programmed death ligand 1 (PDL1) upon cross-presentation of gut flora-derived antigens via major histocompatibility complex (MHC) class I or through the induction of regulatory T cells (T_reg cells) (upon presentation of gut flora-derived antigens to CD4⁺ T cells by MHC class II). f | LSECs clear immune complexes from the circulation via uptake and degradation. g | Periportal LSECs sense gut bacteria and recruit resident macrophages and lymphocytes through chemokine gradients. Besides zone-specific immunomodulation, LSECs might form a hub for communication with resident macrophages through cytokine signalling, thereby altering macrophage phenotypes in a context-dependent manner. h | In hepatocellular carcinoma, malignant hepatocyte-derived vascular endothelial growth factor (VEGF) induces plasmalemma vesicle-associated protein-positive (PLVAP⁺) tumour ECs (TECs) to form an immunosuppressive niche of folate receptor-β-positive (FOLR2⁺) macrophages and T_reg cells. Therapeutic approaches that break LSEC-mediated immune tolerance can impair liver metastasis in preclinical models of metastatic melanoma, breast carcinoma and colon carcinoma. i | In regions of liver fibrosis, atypical chemokine receptor 1-positive (ACKR1⁺) ECs might recruit and modulate/polarize macrophages through the secretion of differentiation factors such as the protein GAS6, growth arrest-specific protein 6 (GAS6) in a contextual manner. Asterisks indicate recent insights which we considered novel for immunomodulatory EC biology. TCR, T cell receptor.

Fig. 2. EC immunomodulation in lung, kidney and brain.

Known and putative insights into endothelial cell (EC) immunomodulation per tissue type. a | In lung cancer, tumour ECs (TECs) are generally immunosuppressive as they display decreased expression levels of antigen-presenting molecules, intercellular adhesion molecule 1 (ICAM1) and various cytokines and chemokines compared with normal lung ECs. Further immunosuppressive features of lung TECs include the elevated expression of FAS ligand (FASL), which induces CD8⁺ T cell apoptosis, and high levels of inhibitory molecules such as PDL1. By contrast, chronic tumour inflammation (indicated by a red background) induces pro-inflammatory high endothelial venule (HEV)-like ECs, which can also occur in other tissues with chronic inflammation. b | In malaria, specific lung immunomodulatory ECs (IMECs) take up and present parasite antigens to CD8⁺ T cells, which then kill ECs by cytolysis, leading to vascular leakage and lung damage. c | Lung IMECs in alveoli are involved in immune cell recruitment and in controlling a delicate balance between immunity and tolerance to pathogens through high expression of major histocompatibility complex (MHC) class II. This possibly involves vascular endothelial growth factor (VEGF), which has an immunosuppressive function; however, the exact underlying mechanisms require further investigation. d | Glomerular ECs with a particularly thick glycocalyx (as depicted, although other ECs generally also have a glycocalyx, which is not shown) impair immune cell infiltration by shielding adhesion/selectin molecules (here represented by cell adhesion molecules (CAMs), which include mainly but not exclusively integrin ligands) on their surface (therefore not visible in the figure). In kidney disease (indicated by the red background), glycocalyx shedding exposes these molecules and promotes immune cell recruitment and inflammation. e | Glomerular ECs clear immune complexes through uptake from the circulation and transcellular transport into the glomeruli for subsequent removal by resident macrophages. f | MHC-I and MHC-II expressing renal IMECs are a target of donor-specific antibodies (DSAs) after kidney transplantation, leading to context-dependent EC activation and altered immunomodulation. g | Renal ECs are phenotypically heterogeneous, owing to their exposure to a heterogeneous microenvironment of differing osmolalities, affecting their inflammatory status. The exact underlying mechanisms and consequences, depending on their anatomical location, require further investigation in vivo. h | The healthy brain is an immune privileged site, and blood–brain barrier (BBB) ECs contribute to this by having tight intercellular junctions and with low or absent expression of adhesion molecules. Upon EC activation in disease (indicated by the red background), the BBB is breached and the brain parenchyma is no longer immune privileged. i | ECs from the aged mouse brain show heterogeneity in (increased) cytokine signalling in arteries, veins and capillaries, possibly increasing immune cell recruitment properties and consequently increasing EC immunomodulatory status and reducing immune privilege. Asterisks indicate recent insights which we considered novel for IMEC biology. HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; mOsm, milliosmoles; PDL1, programmed death ligand 1; TCR, T cell receptor; TGF, transforming growth factor; TLR, Toll-like receptor; T_reg cell, regulatory T cell; VCAM1, vascular cell adhesion molecule 1.