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Review
. 2018 Apr 5:9:527.
doi: 10.3389/fimmu.2018.00527. eCollection 2018.

Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

Adriana Albini  1   2 , Antonino Bruno  1 , Douglas M Noonan  1   3 , Lorenzo Mortara  3
Affiliations
Review

Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

Adriana Albini et al. Front Immunol. .

Abstract

The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves not only cancer cells but also various tumor-associated leukocytes (TALs) and stromal cells. TALs produce chemokines, cytokines, proteases, structural proteins, and microvescicles. Vascular endothelial growth factor (VEGF) and inflammatory chemokines are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In our review, we discuss the regulation of angiogenesis by innate immune cells in the tumor microenvironment, specific features, and roles of major players: macrophages, neutrophils, myeloid-derived suppressor and dendritic cells, mast cells, γδT cells, innate lymphoid cells, and natural killer cells. Anti-VEGF or anti-inflammatory drugs could balance an immunosuppressive microenvironment to an immune permissive one. Anti-VEGF as well as anti-inflammatory drugs could therefore represent partners for combinations with immune checkpoint inhibitors, enhancing the effects of immune therapy.

Keywords: angiogenesis; chemoprevention; immune cells; immunotherapy; tumor microenvironment.

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Figures

Figure 1
Figure 1
Phenotype switch of innate immune cells in cancer. Antitumor/antiangiogenic (green text) and protumor/proangiogenic (red text) features are listed for macrophages, neutrophils, dendritic cells (DC), myeloid precursor cells (MPC), mast cells, natural killer cells (NK), innate lymphoid cells (ILCs), and γδT cells.
Figure 2
Figure 2
Contribution of innate immunity to tumor angiogenesis. Soluble mediators (chemokines, cytokines, and enzymes) within the tumor microenvironment act directly or indirectly as proangiogenic factors produced by macrophages [M2-like tumor-associated macrophages (TAMs)], neutrophils [tumor-associated neutrophil (TAN), N2-like], myeloid-derived-suppressor cells (MDSCs), mast cells, and natural killer (NK) cells.
Figure 3
Figure 3
Pharmacological and immunotherapeutic combination targeting the tumor microenvironment (TME). Immune checkpoint blockers (ICBs) can be employed in diverse pharmacological combinations resulting in clinical benefit for patients. ICBs + antiangiogenic agents result both in inhibition of aberrant angiogenesis and vascular normalization with subsequent efficient T cell infiltration. CCL2 inhibitors combined with chemotherapy dampen induction of M2-like tumor-associated macrophages (TAMs) in the TME and T regulatory (Treg) proliferation. Bisphosphonates + chemotherapy target M2-like TAMs. Anti-Angio, VEGF inhibition and eventually angiopoietin-2 blockade; Asp, aspirin; AT, atenolol; Metf, metformin; Chemo, standard chemotherapeutic drugs.
Figure 4
Figure 4
Effects of vascular endothelial growth factor (VEGF) inhibition combined with immunotherapy in the tumor microenvironment. Immune checkpoint blockers (ICBs) combined with antiangiogenic drugs act synergistically on different cell of innate immunity by (i) reducing VEGF in the tumors that supports angiogenesis; (ii) supporting vascular normalization to stabilize blood vessels and enhance therapeutic agent delivery, T cell infiltration, and activation; (iii) blocking dendritic cells, myeloid-derived suppressor cells, T regulatory (Treg)-mediated immunosuppression.
Figure 5
Figure 5
Examples of effects of repurposed drugs and phytochemicals on natural killer (NK) cell repolarization. The biguanide metformin (Metf), the synthetic triterpenoid 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) and the hop flavonoid xanthohumol (XN) can decrease vascular endothelial growth factor (VEGF) production in non-small cell lung cancer associated NK cells and at the same time can upregulate perforin production. Graphs show data obtained from multicolor flow cytometry analysis of total NK cells (CD45+CD14−CD3−CD56+ cells) from peripheral blood samples of patients with non-small cell lung carcinomas (as in , protocol number 0024138/2013), exposed for 24 h to the compounds at indicated concentrations. These examples sustain the action of anti-inflammatory chemopreventive drugs in innate immune cells repolarization supporting the rationale for future combinations with immunotherapy.
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