TABLE 2.

Factors associated with tumor endothelial cells (TEC) and tumor vessels.

Molecule	Function
Growth factors
VEGF superfamily	central angiogenic factors of tumor angiogenesis (Carmeliet and Jain, 2000; Potente et al., 2011). Induce genetic reprogramming of TECs, changes mode of immune cell interaction and adversely programs the TME (Albini et al., 2018; Maishi et al., 2019). Inhibits the up-regulation of leukocyte adhesion molecules (Griffioen et al., 1999; Dirkx et al., 2003; Flati et al., 2006).
VEGF-C	Central factor of lymphangiognesis (Hsu et al., 2019). Essential for HEV formation (Furtado et al., 2007). Overexpression fosters lymphatic metastasis (Decio et al., 2014; Wang et al., 2014; Yang et al., 2014; Goussia et al., 2018). Activated LECs by VEGF-C suppress tumor specific CD8+ T cells (Lund et al., 2012).
PDGF, HIF1, ANGPT2,	Central angiogenic factors of tumor angiogenesis (Carmeliet and Jain, 2000; Potente et al., 2011).
FGF2	Inhibits the up-regulation of adhesion molecules (ICAM and VCAM) (Griffioen et al., 1999; Dirkx et al., 2003; Flati et al., 2006).
bFGF	Angiocrine factor promoting tumor cell metastasis (Maishi et al., 2019).
EGFL7	Down-regulates adhesion molecules expression and fosters tumor vessel development via NOTCH signaling (Delfortrie et al., 2011; Nichol and Stuhlmann, 2012).
TGFβ	Angiocrine factor contributing to tumor metastasis (Maishi et al., 2019).
Cytokines, interleukines, interferones, chemokines
TNFα	EC activation relies on TNFα and endothelial anergy is characterized by unresponsiveness to TNFα (De Sanctis et al., 2018; Georganaki et al., 2018). Enhances PD-L1 up-regulation on ECs (Georganaki et al., 2018)
IFNγ	Endothelial anergy is characterized by unresponsiveness to IFNγ (De Sanctis et al., 2018). Enhances PD-L1 upregulation on ECs (Georganaki et al., 2018).
IL-6, IL-8	Secreted by activated ECs mediating immune cell trafficking (Aird, 2012; Klein, 2018).
CXCL12/13, CCL19/21, IL-7	Chemokines/interleukines that are associated with the formation of HEVs and TLS (Sautès-Fridman et al., 2019).
CCL2/18, CXCL10/11	Attractant chemokines down-regulated by TECs to prevent immune cell trafficking, therefore mediating immune cell anergy (Griffioen et al., 1996; Huang et al., 2015; Lambrechts et al., 2018).
CXCL4	Chemokine strongly involved in leukocyte activation and endothelial rolling (Ley et al., 2007).
Adhesion molecules
VCAM1, ICAM1 PECAM1, E/P-selectin	Expressed on ECs mediating leukocyte recruitments (Ley et al., 2007). Important gatekeepers of transmigration to the tumor compartment (De Sanctis et al., 2018). Multiple regulation mechanisms by tumor cells/TECs.
Soluble adhesion molecules	sCD146 and Endoglin inhibit TIL recruitment by competitive mechanisms and show direct VEGF-synergistic effects (Rossi et al., 2013; Stalin et al., 2016).
Stemness factors, apoptosis-inducing/preventing molecules proteins
FASL	Expressed by TECs induces apoptosis in CD8+ T cells (Thommen and Schumacher, 2018).
Stemness molecules	TECs upregulate stem cell associated proteins (CD90, MDR1, ALP, Oct-4, and ALDH), which are associated with increased self renewal and high proliferative potential (Ohga et al., 2012; Ohmura-Kakutani et al., 2014; Hida et al., 2017)
Immune checkpoints
PD-L1/2, TIM3	Expressed by TECs and promotes T cell arrest (Georganaki et al., 2018).
IDO1	Immune-regulatory molecule expressed by TECs in response to IFNγ restricting activation and inducing apoptosis of T cells (Georganaki et al., 2020).
Antigen-presenting molecules
MHC I, II	Frequently expressed by ECs but lacking the co-stimulatory molecules (CD80 and CD86) (Shiao et al., 2007). MHC molecules can be down-regulated by TECs contributing to immune-evasion (Goveia et al., 2020).
Other
NO	Affects leukocyte recruitment under malignant conditions (De Caterina et al., 1995). Directly suppresses effector T cells (De Sanctis et al., 2018). NO-antagonists restores T cell adhesion by up-regulation of adhesion molecules (Bouzin et al., 2007; Buckanovich et al., 2008).
ET1	Associated with ICAM1 expression and decreases TIL influx (Spinella et al., 2002; Buckanovich et al., 2008).
STING	Highly expressed on ECs of HEVs and impacts the expression of adhesion molecules (Demaria et al., 2015; Yang et al., 2019).
CLEVER1	Favors the selective influx of Treg and immuno-suppressive TAM (Nummer et al., 2007; Karikoski et al., 2014).
Biglycan	Preferentially expressed by high metastatic tumors and allows toll-like receptor expressing tumor cells to metastasize hematogenously (Maishi et al., 2016).
Galectins	Glycan-binding endogenous lectins which sustain tumor angiogenesis via autocrine and paracrine signaling (Elola et al., 2018). Directly interact with VEGFR2, bFGF, VEGFR3 and associated with resistance to anti-angiogenic therapies (Markowska et al., 2010; Markowska et al., 2011; Zhao et al., 2011; Laderach et al., 2013; Chen et al., 2016).
Jag1	Expressed by TECs to generate malignant vascular niche, which is associated with aggressive course and resistance to chemotherapy (Cao et al., 2016).
Slit2	Tumor-suppressive factor directly down-regulated by TECs via paracrine EphA2 signaling (Brantley-Sieders et al., 2011).