The Emerging Roles of Pericytes in Modulating Tumor Microenvironment

Abstract

Pericytes (PCs), known as mural cells, play an important blood vessel (BV) supporting role in regulating vascular stabilization, permeability and blood flow in microcirculation as well as blood brain barrier. In carcinogenesis, defective interaction between PCs and endothelial cells (ECs) contributes to the formation of leaky, chaotic and dysfunctional vasculature in tumors. However, recent works from other laboratories and our own demonstrate that the direct interaction between PCs and other stromal cells/cancer cells can modulate tumor microenvironment (TME) to favor cancer growth and progression, independent of its BV supporting role. Furthermore, accumulating evidence suggests that PCs have an immunomodulatory role. In the current review, we focus on recent advancement in understanding PC's regulatory role in the TME by communicating with ECs, immune cells, and tumor cells, and discuss how we can target PC's functions to re-model TME for an improved cancer treatment strategy.

Keywords: angiogenesis; immunomodulation; mural cell; pericyte; tumor microenvironment.

FIGURE 1

Schematics diagram represents the emerging immunomodulatory role of pericytes in tumor microenvironment. ➀Recruitment of tumor-associated macrophage (TAM). PDGF-BB-stimulated PCs release IL-33 to recruit more TAMs. ➁ Increased co-migration of TAMs and tumor cells. PC-derived chemokine CXCL12 (SDF-1) contributes to the co-migration of TAMs and tumor cells during innate immune response. ➂ Increased myeloid-derived suppressor cells (MDSCs) transmigration. PC loss causes leaky blood vessels and inadequate oxygen supply leading to tumor hypoxia, which then induces IL-6 expression in tumor cells to increase MDSC transmigration, resulting in suppression of the T cell-mediated anti-tumor response. ➃ Induced CD4⁺ T cell anergy. Tumor PCs act as negative regulators of CD4⁺ T cell activity. ➄ Inhibition of mitogen- and allogeneic-stimulated T cell proliferation. Human malignant glioma-derived pericyte (HMGP) releases PGE2, NO, sHLA-G, HGF, and TDF-β to suppress T cell proliferation, while CD90-positive PCs may function as suppressors of the infiltration of leukocytes and CD8⁺ T cells in malignant glioma. ➅ Inhibition of T cell and antigen presenting cell activity, and increased recruitment of regulatory T cells. Glioblastoma conditioned-pericyte (GBC-PC) not only negatively regulates T cell and antigen presenting cell (APC) but also recruits regulatory T cell (T reg). ➆ Regulation of blood vessel normalization and immune cell infiltration. In the positive feedback loop between type 1 T helper (T_H1) and blood vessel normalization, PC coverage has a certain impact on T_H1-mediated immune cell infiltration. ➇ Enhanced CD8⁺ T cell recruitment and malignant B cell migration. Perivascular cell derived CXCL9 and CXCL12 can recruit CD8⁺ T cell effectors by binding to their corresponding receptor CXCR3 and CXCR4 respectively. Besides, CXCL9 forms a heterocomplex with CXCL12, which then enhances CXCR4-dependent malignant B cell migration to accumulate on the vessel wall (Created with BioRender.com).