Intertwined regulation of angiogenesis and immunity by myeloid cells

Abstract

Angiogenesis is a hallmark of cancer because its induction is indispensable to fuel an expanding tumor. The tumor microenvironment contributes to tumor vessel growth, and distinct myeloid cells recruited by the tumor have been shown not only to support angiogenesis but also to foster an immune suppressive environment that supports tumor expansion and progression. Recent findings suggest that the intertwined regulation of angiogenesis and immune modulation can offer therapeutic opportunities for the treatment of cancer. We review the mechanisms by which distinct myeloid cell populations contribute to tumor angiogenesis, discuss current approaches in the clinic that are targeting both angiogenic and immune suppressive pathways, and highlight important areas of future research.

Figure 1. Hypoxia mediates recruitment of angiogenic myeloid cells that drive both tumor progression and resistance to antiangiogenic therapy

Solid tumors eventually reach a size that, due to oxygen and nutrient diffusion limits, cannot be sustained by the existing vasculature. This results in a decrease in oxygen tension within the tumor. Hypoxia positively regulates the expression of a variety of genes in tumor cells, many of which result in the infiltration or accumulation of angiogenic myeloid cells. For example, tumor-derived VEGF, CSF-1, MCP-1, and SDF1α recruit angiogenic monocytes including macrophages and Gr1⁺ G-MDSC and MMDSC into tumors; CXCL2 recruits angiogenic neutrophils and monocytes; Ang2 recruits angiogenic Tie2-expressing monocytes and macrophages (TEMs); IL-4 and IL-6 induce the differentiation of infiltrating monocytes into angiogenic and immune-suppressive macrophages; also, Sema3A brings Nrp1-expressing TAMs into hypoxic regions where they are reprogrammed to an angiogenic and immune-suppressive phenotype. Tumor-associated MDSC, TAM, TEMS, and neutrophils then secrete or liberate sequestered angiogenic factors, of which VEGF is dominant to facilitate neovascularization. This in turn leads to continued tumor growth and disease progression. Blocking persistent vessel growth can blunt tumor growth; however, this increases hypoxia and hypoxia-induced gene expression. Thus, tumors reinitiate the recruitment of angiogenic MDSC, TAM, TEMS, and neutrophils via the secretion of hypoxia- regulated factors, many of which drive myeloid-cell recruitment during normal tumor progression. These cells then reinstatement tumor angiogenesis via VEGF-independent pathways, thereby conferring tumor resistance to VEGF-blockade. Abbreviations: VEGF, vascular endothelial growth factor; Sema3A, semaphorin-3A; MCP-1, monocyte chemotactic protein-1; CSF-1, colony stimulating factor-1; CXCL2, (C-X-C motif) ligand 2; IL-6, interleukin-6; IL-4, interleukin-4; Ang2, angiopoietin 2; SDF1α, stromal-derived factor 1α; GCSF, granulocyte colony stimulating factor; PlGF, placental growth factor; G- or M- MDSC, granulocytic or monocytic myeloid-derived suppressor cell; TAN, tumor-associated neutrophil; TAM, tumor-associated macrophage; TEM, Tie2⁺-expressing macrophage.

Figure 2. VEGF regulates intratumoral immune response

VEGF promotes tumor growth by both inducing angiogenesis and suppressing anti-tumor immunity. VEGF inhibits the adhesion of T-cells to the luminal surfaces of blood vessels by blocking TNFα-induced expression of VCAM and ICAM, thereby blocking T-cell extravasation into the tumor. VEGF also blocks dendritic cell function by inhibiting dendritic cell maturation and inducing PDL1 expression on mature dendritic cells. VEGF also inhibits the proliferation and effector function of cytotoxic T-cells, while inducing Treg proliferation. Tregs secrete high levels of cytokines and growth factors, including IL-10, IL-4, IL-13, TGFβ1, GM-CSF, and CSF-1, which, like VEGF itself, drive recruitment and infiltration of angiogenic and immune-suppressive MDSC and macrophages. MDSC and macrophages then produce reactive oxygen species, nitric oxide, and arginase to suppress T-cell proliferation, viability, and activity. In contrast, inhibition of VEGF should restore many of these phenotypes. VEGF inhibition enables dendritic cell maturation and function, which leads to an increase in intratumoral effector T-cell numbers. Furthermore, VEGF-blockade should enable the endothelium to facilitate T-cell infiltration. Presumably, VEGF-blockade also results in an increase in Th1 cytokine-secreting tumoricidal and immune-supporting myeloid cells such as macrophages. Altogether, VEGF-blockade should unleash the anti-tumor immune response and leads to increased tumor cell apoptosis. However, the antiangiogenic effect of VEGF-blockade results in hypoxia, which drives the recruitment and polarization of immune-suppressive and angiogenic myeloid populations. Thus, therapeutic approaches aimed at activating immune response may enhance or prolong the efficacy of antiangiogenic therapy. Abbreviations: VEGF, vascular endothelial growth factor; PDL1/2, programmed death ligand 1/2; VCAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule; iDC, immature dendritic cell; DC, dendritic cell; CTL, cytotoxic T-cell; Treg, regulatory T-cell; ROS, reactive oxygen species; NO, nitric oxide; Arg1, arginase-1; IL-10, -4, - 13, -12, -23, -1b, -8, interleukin-10, -4, -13, -12, -23, -1b, -8; TGFβ1, transforming growth factor-β1; GM-CSF, granulocyte/monocyte-colony stimulating factor; CSF-1, colony stimulating factor-1; G- or M- MDSC, granulocytic or monocytic-myeloid derived suppressor cell; TAM, tumor-associated macrophage; FGF-1, -2, -13, fibroblast growth factor-1, -2, -13; PDGF, platelet-derived growth factor; TNFα, tumor necrosis factor-α; NK-cell, natural killer cell; Th1, T-helper 1.