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

Adriana Albini,Antonino Bruno,Douglas M Noonan,Lorenzo Mortara

doi:10.3389/fimmu.2018.00527

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.

Highlights

The “gradient” of phenotype, genetic, and epigenetic features of transformed cells inside the tumor gives rise to the most known and studied tumor heterogeneity, the “intrinsic” one
IL-17-dependent STAT3/GIV signaling pathway is responsible for vascular endothelial growth factor (VEGF) release from cancer cells and promotion of tumor angiogenesis, and GIV expression positively correlates with IL-17+ cell presence and increased microvessel densities and predicts poor survival of non-small cell lung carcinomas (NSCLC) patients [154]
We showed that the CD56brightCD16− natural killer (NK) cells, the predominant subset infiltrating NSCLC tissues and a minor subset in adjacent lung and peripheral blood, are associated with VEGF, placental growth factor (PlGF), and IL-8 production (Figure 2)

Summary

INTRODUCTION

The “gradient” of phenotype, genetic, and epigenetic features of transformed cells inside the tumor gives rise to the most known and studied tumor heterogeneity, the “intrinsic” one. Neutrophils produce either proangiogenic or antiangiogenic factors [75,76,77,78,79], and in some cases, such as in the early phases of lung cancers, they can exert important T cell stimulatory, antitumor functions [80] They are characterized by a terminally differentiated phenotype and a short half-life, these cells are endowed with a certain kind of plasticity and in murine tumor models they are able to differentiate in two distinct subsets: neutrophils type 1 (N1) with antimicrobial functions, and tumorassociated neutrophils (TANs or N2) endowed with protumor and proangiogenic features (Figure 2) in response to TGFβ [81, 82]. RegDCs and MDSCs have cell-type specific functional properties, their capability of regulating tumor angiogenesis in the TME appears similar to the one of M2-like TAMs and N2 neutrophils, leading to production of several soluble factors such as VEGF, FGF2, BV8, and MMP9 [130]

MAST CELLS

INNATE LYMPHOID CELLS

NK CELLS

PHARMACOLOGICAL AND IMMUNOTHERAPEUTIC COMBINATION TARGETING THE TME

Findings

CONCLUSION