Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells

Abstract

The establishment of immune tolerance during Glioblastoma Multiforme (GBM) progression, is characterized by high levels expression of anti-inflammatory cytokines, which suppress the function of tumor assocciated myeloid cells, and the activation and expansion of tumor antigen specific T cells. However, the mechanisms underlying the failed anti-tumor immune response around the blood vessels during GBM, are poorly understood. The consequences of possible interactions between cancer cells and the perivascular compartment might affect the tumor growth. In this work we show for the first time that GBM cells induce immunomodulatory changes in pericytes in a cell interaction-dependent manner, acquiring an immunosuppresive function that possibly assists the evasion of the anti-tumor immune response and consequently participates in tumor growth promotion. Expression of high levels of anti-inflammatory cytokines was detected in vitro and in vivo in brain pericytes that interacted with GBM cells (GBC-PC). Furthermore, reduction of surface expression of co-stimulatory molecules and major histocompatibility complex molecules in GBC-PC correlated with a failure of antigen presentation to T cells and the acquisition of the ability to supress T cell responses. In vivo, orthotopic xenotransplant of human glioblastoma in an immunocompetent mouse model showed significant GBM cell proliferation and tumor growth after the establishment of interspecific immunotolerance that followed GMB interaction with pericytes.

Glioblastoma‐activated pericytes support tumor growth via immunosuppression

“…Pericytes are associated to cerebral blood vessels. The study of Valdor and colleagues now reveals a novel very important function of pericytes during glioblastoma development . Glioblastoma‐activated pericytes increase the expression of anti‐inflammatory molecules, such as IL ‐10, TGF β, and MHC ‐ II , favoring immunosuppression and tumor growth.…”

“…The study by Valdor et al. (2017) demonstrates that glioblastoma‐activated pericytes release IL‐10 and TGF β . Nevertheless, it still remains poorly explored whether other factors produced by brain pericytes are important for the support of glioblastoma growth.…”

“…The method of pericyte isolation used by Valdor et al (2017) could result in the presence of other perivascular cells in these cultures. To avoid this, isolation by sorting based on several molecular membrane markers would be preferred.…”

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

“…Although interactions between metastatic cells and CECs, astrocytes, or microglia are relatively well characterized [6], our knowledge about the role of pericytes is restricted to indirect effects on tumor cells, including regulation of blood-tumor barrier permeability [28] and secretion of connective tissue proteins [21]. By remodeling the perivascular niche [29], increasing angiogenesis [29], and acquiring an immunosuppressive function [31,32], pericytes have undisputed roles in promoting primary brain tumors. Therefore, we hypothesized that pericytes might facilitate progression of brain metastases as well.…”

Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

“…The expression of anti-inflammatory molecules, such as IL-10, TGF-β, and MHC-II, is increased in glioblastoma-activated pericytes, thus favoring immunosuppression and tumor growth [106]. To date, it still remains to be elucidated what the other molecules (growth factors and/or cytokines) produced by brain pericytes supporting the tumor growth are.…”