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

Rut Valdor, David García-Bernal, Dolores Riquelme, Carlos M. Martinez, Jose M. Moraleda, Ana Maria Cuervo, Fernando Macian, Salvador Martinez

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20655-20665
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number41
DOIs
StatePublished - Oct 8 2019

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Keywords

  • Chaperone-mediated autophagy
  • Glioblastoma
  • Immunosuppressive function
  • Pericytes
  • Tumor

ASJC Scopus subject areas

  • General

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