Table 2.

Immunomodulatory effects of selected anti-angiogenic factors.

Anti-Angiogenic Agent		Functions
VEGF-A antibody	Bevacizumab	Decreases MDSCs and Tregs accumulation [124,125].
		Enhances CTLs responses: It was shown to (a) increases the peripheral B- and T-cell compartments [126], (b) correlate with an increase in activated (CD8+ CD62 L+) CTLs, long-term effector memory (CD8+ CD27+) and central-memory (CD8+ C45 RA-CCR7+) CTLs [127,128] and (c) enhance antigen-specific T-cell migration [129]
		Improves DCs maturation and activation: It was shown to increase the percentage of activated and mature myeloid derived DC [127,130], and to reverse the VEGF inhibitory effects on DCs [131].
		Induces vessel normalization, increases tumor vascular expression of ICAM1 and VCAM1 and T-cell tumor infiltration [132,133,134,135].
VEGFR1–3, PDGFR, c-KIT, FLT-3, CSF-1 R and RET mtTKI	Sunitinib	Enhances the Th1 immune response and inhibits the immunosuppressive Th2 response [136,137].
		Decreases MDSCs and tumor Tregs compartments [136,137,138,139,140].
		Induces endothelial activation and T-cell recruitment, by enhancing the expression of chemokines and adhesion molecules on tumor endothelial cells, resulting in a higher number of CD3+ T-cells in the tumor [141,142].
		Enhances the percentage and number of intratumoral CD4 and CD8 T-cells and decreases the expression of inhibitory molecules (i.e., CTLA-4 and PD-1) on TILs [141,143].
VEGFR1–3, PDGFR and c-KIT mtTKI	Axitinib	Enhances the CD8+ T cells compartment [144].
		Increases the antigen-presenting function of intratumoral DCs [145].
		Reduces MDSCs levels [144] and inhibits their suppressive capacity [145].
VEFGR2 TKI	Apatinib	Increases the infiltration of CD8+ T cells and reduces the recruitment of TAMs [146].
		Reduces the expression levels of inhibitory checkpoint molecules, such as Lag-3, PD-1 and Tim3 in CD8+ T cells [147].
		Enhances the production of IFN-γ and IL-2 and promote the cytotoxicity of T cells [147].
Raf, VEGFR2, PDGFR, FLT3, RET and c-KIT mtTKI	Sorafenib	Reverses immunosuppression: It decreases MDSCs levels [148], Tregs and Th2-cells [149], and inhibits Tregs functions [150].
		Upregulates tumor-specific effector T-cells functions [150] and induces Th1 dominance [149].
		Reverses the VEGF inhibitory effects on DCs [131], but was also shown to inhibit the function of DCs [151] and inhibit the induction of antigen-specific T cells [151].

Abbreviations: (mt)TKI: (multi-target) tyrosine kinase inhibitor; PDGFR: platelet derived growth factor receptor; VEGF(R): vascular endothelial growth factor (receptor); FLT3: Fms-like tyrosine kinase-3; CSF-1 R: colony stimulating factor receptor; RET: glial cell-line derived neurotrophic factor receptor; DCs: dendritic cells; ICAM1: intercellular adhesion molecule-1; VCAM1: vascular cell adhesion molecule-1; Th(1/2): T helper cell (1/2); Lag3: lymphocyte activation gene 3 protein; Tim3: T-cell immunoglobulin mucin receptor 3; PD-1: programmed cell death protein 1; CTLs: cytotoxic T-lymphocytes; Tregs: T-regulatory cells; MDSCs: myeloid derived suppressor cells; TAMs; tumor associated macrophages.