Abstract

The tumor microenvironment (TME) plays a central role in cancer development and progression. It represents a complex network of cancer cell (sub-)clones and a variety of stromal cell types. Recently, new technology platforms shed light on the cellular composition of the TME at very high resolution and identified a complex landscape of multi-lineage immune cells (e.g., T and B lymphocytes, myeloid cells, and dendritic cells), cancer associated fibroblasts (CAF) and tumor endothelial cells (TECs). A growing body of evidence suggests that metabolically, genetically and on their transcriptomic profile TECs exhibit unique phenotypic and functional characteristics when compared to normal endothelial cells (NECs). Furthermore, the functional role of TECs is multifaceted as they are not only relevant for promoting tumor angiogenesis but have also evolved as key mediators of immune regulation in the TME. Regulatory mechanisms are complex and profoundly impact peripheral immune cell trafficking into the tumor compartment by acting as major gatekeepers of cellular transmigration. Moreover, TECs are associated with T cell priming, activation and proliferation by acting as antigen-presenting cells themselves. TECs are also essential for the formation of tertiary lymphoid structures (TLS) within the tumor, which have recently been associated with treatment response to checkpoint antibody therapy. Further essential characteristics of TECs compared to NECs are their high proliferative potential as well as greatly altered gene expression profile (e.g., upregulation of pro-angiogenic, extracellular matrix remodeling, and stemness genes), which results in enhanced secretion of immunomodulatory cytokines and altered cell-surface receptors [e.g., major histocompatibility complex (MHC) and immune checkpoints]. The TEC phenotype may be rooted in an aggressive tumor micro-milieu based on cellular stress via hypoxia and reactive oxygen species (ROS). Vice versa TECs might modulate TME immunogenicity thereby fostering cancer-associated immune suppression. This review aims to elucidate the currently emergent pathophysiological aspects of TECs with a particular focus on their potential role as regulators of immune cell function in the TME. It is a main future challenge to deeply characterize the phenotypic and functional profile of TECs to illuminate their complex role within the TME. The ultimate goal is the identification of TEC-specific drug targets to improve cancer (immuno-)therapy.

Highlights

  • Cancer cells are tightly embedded within the tumor microenvironment (TME) and are in constant interaction with surrounding stromal cells, encompassing multi-lineage immune cells such as antigen-presenting cells (APC), T and B lymphocytes and myeloid cells, cancer-associated fibroblasts (CAFs) and endothelial cells (ECs)

  • The vasoconstrictive peptide Endothelin 1 (ET1), known for its direct effect on angiogenesis via VEGF and HIF1 (Spinella et al, 2002), is associated with ICAM1 expression and the decreased presence of tumor infiltrating leukocytes (TIL) (Buckanovich et al, 2008). Another mechanism of endothelial anergy includes the secretion of soluble adhesion molecules by tumor cells (MCAM/sCD146 and Endoglin) that indirectly inhibit TIL recruitment by competing with EC bound-receptors (Rossi et al, 2013; Stalin et al, 2016) and by direct VEGF-synergistic interactions with tumor angiogenesis (Zheng et al, 2009)

  • tumor endothelial cells (TECs) are central players orchestrating the TME. They phenotypically differ from normal endothelial cells (NECs), are highly proliferative, exhibit genetic instability and a stemness gene signature

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Summary

INTRODUCTION

Cancer cells are tightly embedded within the tumor microenvironment (TME) and are in constant interaction with surrounding stromal cells, encompassing multi-lineage immune cells such as antigen-presenting cells (APC), T and B lymphocytes and myeloid cells, cancer-associated fibroblasts (CAFs) and endothelial cells (ECs). A central therapeutic focus lies upon reversing the intrinsic cancer-associated immune escape, which involves numerous innate and adaptive immune responses as well as tumor neoangiogenesis. The latter is regulated by the cancer cell itself, and by the surrounding cellular components of the TME (Galon and Bruni, 2020). The knowledge on TEC phenotypes is rapidly growing, their functional role in cancer-associated immune escape including response to established immune and antiangiogenic therapies still needs to be specified in detail.

TEC morphology Metabolism Cytogenetics Molecular genetics
Growth factors
Adhesion molecules
Stemness molecules
Immune checkpoints
Tumor Endothelial Cells
TECs AND THEIR IMMUNOREGULATORY PROPERTIES
Tumor Endothelial Anergy
TEC Affects T Cell Priming and Migration
TEC as Antigen Presenting Cells
CONCLUSION
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