@article{82e67188745c4f6b9c346ea35f95fedb,
title = "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{\textquoteright}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.",
keywords = "Chaperone-mediated autophagy, Glioblastoma, Immunosuppressive function, Pericytes, Tumor",
author = "Rut Valdor and David Garc{\'i}a-Bernal and Dolores Riquelme and Martinez, {Carlos M.} and Moraleda, {Jose M.} and Cuervo, {Ana Maria} and Fernando Macian and Salvador Martinez",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Pablo Pelegr{\'i}n{\textquoteright}s laboratory at the Experimental Surgery Unit, Biomedical Research Institute of Murcia-Arrixaca, for his always kind help providing tools for this study; Prof. Pedro Aparicio at the Immunology Department of University of Murcia for all his kind and helpful discussions about this study; and the Anatomy Department of the College of Medicine, the Microscopy and Cell Culture facilities at the University of Murcia, and the Animal facility of Biomedical Research Institute of Murcia-Arrixaca, for their technical support. This work was funded mainly by Ministerio de Econom{\'i}a y Competitividad de Espa{\~n}a (MINECO) SAF2015-73923-JIN and Fondo Europeo de Desarrollo Regional/Union Europea (AEI/FEDER/UE) (to R.V.). It was supported partially by Mobility Seneca Foundation Grant “Programa Jimenez de la Espada, 19667/EE/14 (to R.V.); Seneca 20840/PI/18 (to R.V.); ISCIII/Red de Terapia Celular, TERCEL RD16/0011/0010 and RD16/0011/0001 (to S.M. and J.M.M.); and NIH P01 AG031782 (to F.M. and A.M.C.). Funding Information: We thank Dr. Pablo Pelegr?n?s laboratory at the Experimental Surgery Unit, Biomedical Research Institute of Murcia-Arrixaca, for his always kind help providing tools for this study; Prof. Pedro Aparicio at the Immunology Department of University of Murcia for all his kind and helpful discussions about this study; and the Anatomy Department of the College of Medicine, the Microscopy and Cell Culture facilities at the University of Murcia, and the Animal facility of Biomedical Research Institute of Murcia-Arrixaca, for their technical support. This work was funded mainly by Ministerio de Econom?a y Competitividad de Espa?a (MINECO) SAF2015-73923-JIN and Fondo Europeo de Desarrollo Regional/Union Europea (AEI/FEDER/UE) (to R.V.). It was supported partially by Mobility Seneca Foundation Grant ?Programa Jimenez de la Espada, 19667/EE/14 (to R.V.); Seneca 20840/PI/18 (to R.V.); ISCIII/Red de Terapia Celular, TERCEL RD16/0011/0010 and RD16/0011/0001 (to S.M. and J.M.M.); and NIH P01 AG031782 (to F.M. and A.M.C.). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
month = oct,
day = "8",
doi = "10.1073/pnas.1903542116",
language = "English (US)",
volume = "116",
pages = "20655--20665",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "41",
}
