Current Status of Lymphangiogenesis: Molecular Mechanism, Immune Tolerance, and Application Prospect

Abstract

The lymphatic system is a channel for fluid transport and cell migration, but it has always been controversial in promoting and suppressing cancer. VEGFC/VEGFR3 signaling has long been recognized as a major molecular driver of lymphangiogenesis. However, many studies have shown that the neural network of lymphatic signaling is complex. Lymphatic vessels have been found to play an essential role in the immune regulation of tumor metastasis and cardiac repair. This review describes the effects of lipid metabolism, extracellular vesicles, and flow shear forces on lymphangiogenesis. Moreover, the pro-tumor immune tolerance function of lymphatic vessels is discussed, and the tasks of meningeal lymphatic vessels and cardiac lymphatic vessels in diseases are further discussed. Finally, the value of conversion therapy targeting the lymphatic system is introduced from the perspective of immunotherapy and pro-lymphatic biomaterials for lymphangiogenesis.

Keywords: immune tolerance; immunotherapy; lymphangiogenesis; meningeal lymphatic vessels; myocardial infarction; tumor metastasis.

Figure 1

The function of lymphatic system.

Figure 2

Relationship between VEGFC- and PROX1-related signaling pathways and lipid metabolism. SOX18 and COUP-TFII promote PROX1 transcription and the differentiation of embryonic venous endothelial cells into LECs. Fatty acids enter LECs and aggregate into lipid droplets that are then transported to mitochondria by autophagy to provide the free fatty acids required for FAO. AcCoA is produced by fatty acid oxidation, and acetyltransferase p300 acetylates histone H3K9ac of PROX1 to promote VEGFR3 expression. Prox1 promotes CpT1A-dependent fatty acid β-oxidation to further increase AcCoA production. In addition to interacting with PROX1, VEGFC/VEGFR3 signaling can also regulate the expression of ribosomal RNA through Ddx21 and inhibit the positive regulation of the cell cycle by p53, thus promoting the proliferation of LECs. Endogenous pro-VEGFC must be cleaved by CCBE1/Adamts3 and Adamts14/Adamts2 to become mature VEGFC, which can bind to VEGFR3 and regulate PROX1 expression.

Figure 3

Molecular mechanism of the effect of mechanical signals on LECs. Transcription factors GATA2, FOXC2, and FOXO1 are important target molecules in LECs regulated by mechanical signaling. In response to OSS signaling, VE-cadherin can bind to β-catenin to drive FOXC2 and PROX1 transcription and can phosphorylate VEGFR3 to activate the P13/AKT pathway. AKT phosphorylation can inhibit the transcription of FOXO1 and induce the expression of FOXC2. FOXO1 inhibits the activity of FOXC2 and Cx37 by regulating PRDM1 and inhibits valvular lymphatic production. FOXC2 inhibits the Hippo pathway and downstream YAP1/TAZ to aid in the quiescence and survival of LECs. In addition, FOXC2 cooperates with PROX1 and FOXP2 to regulate Cx37 and Cn/NFATc1 to control LEC cytoskeleton remodeling and cell alignment in response to OSS. OSS and soft ECM stiffness can activate transcription of GATA2. GATA2 mediates LEC migration and polarity via FAT4 on the one hand and migration and survival via NRP2/VEGFR3 on the other.

Figure 4

Mechanisms of immune tolerance mediated by the lymphatic system. IFN-γ signaling promotes the expression of MHC-I molecules and PD-L1 by LECs, which present immune checkpoints such as CTLA-4, PD-1, and CD80 expressed by CD8⁺ T cells activated by foreign antigens. These CD8⁺ T cells undergo apoptosis. LECs expressing PTA also result in the loss of CD8⁺ T cells. LECs secrete immunosuppressive molecules such as TGF-β, IDO, and INOS to inhibit CD8⁺ T cells and DCs. LECs can inhibit DC maturation. Presentation of antigens by LECs expressing MHC-II activates Treg cells and inhibits effector T cells. The expression of VEGFR3 by macrophages and VEGFC can promote the polarization of macrophages to the M2 type, and M2-type macrophages can inhibit the proliferation of effector T cells. LNSCs obtain pMHC-II from DCs to inhibit CD4⁺ T function.