Rut VALDOR ALONSO¹, DAVID GARCIA BERNAL², Dolores Riquelme Dólera³, CARLOS MANUEL MARTINEZ CACERES⁴, Jose Maria MORALEDA JIMÉNEZ², Ana Maria Cuervo⁵, Fernando Macian⁶, SALVADOR MARTINEZ PEREZ⁷

(1) AUTOFAGIA, RESPUESTA INMUNE Y TOLERANCIA EN PROCESOS PATOLÓGICOS, IMIB, España
(2) TRASPLANTE HEMATOPOYÉTICO / TERAPIA CELULAR, IMIB, España
(3) Técnico de laboratorio, 30565, España (Región de Murcia)
(4) PLATAFORMA DE PATOLOGÍA, IMIB, España
(5) Albert Einstein College of Medicine. Developmental molecular biology, Institute for aging studies. Bronx, New York, 10461, Estados Unidos
(6) Albert Einstein College of Medicine. Pathology Department, Institute for aging studies. Bronx, New York, 10461, Estados Unidos, Estados Unidos
(7)

PMID: 31548426
Referencia: Valdor R, García-Bernal D, Riquelme D, Martinez CM, Moraleda JM, Cuervo AM, Macian F, Martinez S. Glioblastoma ablates pericytes antitumor immune function through aberrant up-regulation of chaperone-mediated autophagy. Proc Natl Acad Sci U S A. 2019 Sep 23. pii: 201903542. doi: 10.1073/pnas.1903542116. [Epub ahead of print] PubMed PMID: 31548426.
ISSN: 0027-8424
Revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Factor de impacto (2017): 11.1
Cuartil: 1 PRIMER DECIL

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.

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 upregulation 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.