Glioblastoma ablates pericytes antitumor immune function through aberrant up-regulation of chaperone-mediated autophagy

Abstract

The contractile perivascular cells, pericytes (PC), are hijacked by glioblastoma (GB) to facilitate tumor progression. PC’s protumorigenic function requires direct interaction with tumor cells and contributes to the establishment of immunotolerance to tumor growth. Cancer cells up-regulate their own chaperone-mediated autophagy (CMA), a process that delivers selective cytosolic proteins to lysosomes for degradation, with pro-oncogenic effects. However, the possible impact that cancer cells may have on CMA of surrounding host cells has not been explored. We analyzed the contribution of CMA to the GB-induced changes in PC biology. We have found that CMA is markedly up-regulated in PC in response to the oxidative burst that follows PC–GB cell interaction. Genetic manipulations to block the GB-induced up-regulation of CMA in PC allows them to maintain their proinflammatory function and to support the induction of effective antitumor T cell responses required for GB clearance. GB-induced up-regulation of CMA activity in PC is essential for their effective interaction with GB cells that help tumor growth. We show that CMA inhibition in PC promotes GB cell death and the release of high immunogenic levels of granulocyte-macrophage colony stimulating factor (GM-CSF), through deregulation of the expression of cell-to-cell interaction proteins and protein secretion. A GB mouse model grafted in vivo with CMA-defective PC shows reduced GB proliferation and effective immune response compared to mice grafted with control PC. Our findings identify abnormal up-regulation of CMA as a mechanism by which GB cells elicit the immunosuppressive function of PC and stabilize GB–PC interactions necessary for tumor cell survival.

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

“…In a mouse model of xenografted GB cells, PC with impaired CMA, by knocking out Lamp2a expression, promote antigen-specific T cell infiltration in the peritumoral areas, resulting into tumor elimination. FOXP3 + Tregs populations hardly were infiltrated in those areas and reduced expression of immune checkpoints, such as CTLA-4 and PD-1 in T cells, was detected [36]. This work supports that CMA inhibition in specific cells of the innate immune response of the brain, such as PC, may be an effective approach to treat this aggressive disease (Figure 2).…”

“…PC are located on the abluminal vessel wall, regulating vascular tone and morphology, and represent an immunological defense in the brain modulating neuroinflammation [33][34][35]. However, PC also express PD-L1 and acquire an immunosuppressive phenotype upon GB interaction, assisting GB to escape the immune system recognition [13,36].…”

“…Importantly, up-regulated CMA may also assist chemoresistance of GB, making them more resistant to different stressors such as oxidative stress, hypoxia or even DNA damage agents [4,115]. Up-regulation of CMA in GB cells that are in contact with perivascular areas, not only favors their proliferation, but it may even interfere with the aberrant CMA up-regulation in tumor surrounding cells that benefits tumor survival and affects anti-tumor immune microenvironment responses [36].…”

“…Recent studies of our group have revealed a new role of CMA in the immune function of perivascular cells PC during GB progression and through interaction with tumor cells [13,36]. PC initiate aberrant degradation of proteins in response to a burst of oxidative stress upon GB interaction, changing the levels of secretion of several cytokines and of growth factor release, in a manner that supports tumor cell proliferation and GB survival.…”

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.…”