Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy

Serena Pellegatta, Barbara Savoldo, Natalia Di Ianni, Cristina Corbetta, Yuhui Chen, Monica Patané, Chuang Sun, Bianca Pollo, Soldano Ferrone, Francesco DiMeco, Gaetano Finocchiaro, Gianpietro Dotti

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Abstract

The heterogeneous expression of tumor-associated antigens limits the efficacy of chimeric antigen receptor (CAR)- redirected T cells (CAR-Ts) for the treatment of glioblastoma (GBM). We have found that chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed in 67% of the GBM specimens with limited heterogeneity. CSPG4 is also expressed on primary GBM-derived cells, grown in vitro as neurospheres (GBM-NS), which recapitulate the histopathology and molecular characteristics of primary GBM. CSPG4.CAR-Ts efficiently controlled the growth of GBM-NS in vitro and in vivo upon intracranial tumor inoculation. Moreover, CSPG4.CAR-Ts were also effective against GBM-NS with moderate to low expression of CSPG4. This effect was mediated by the in vivo up-regulation of CSPG4 on tumor cells, induced by tumor necrosis factor-a (TNFα) released by the microglia surrounding the tumor. Overall, the constitutive and TNFα-inducible expression of CSPG4 in GBM may greatly reduce the risk of tumor cell escape observed when targeted antigens are heterogeneously expressed on tumor cells.

Original languageEnglish
Article numbereaao2731
JournalScience Translational Medicine
Volume10
Issue number430
DOIs
Publication statusPublished - Feb 28 2018

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Antigen Receptors
Glioblastoma
Cell- and Tissue-Based Therapy
Tumor Necrosis Factor-alpha
Neoplasms
Tumor Escape
chondroitin sulfate proteoglycan 4
Microglia
Neoplasm Antigens
T-Cell Antigen Receptor
Up-Regulation
Antigens
Growth

ASJC Scopus subject areas

  • Medicine(all)

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Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres : Implications for CAR-T cell therapy. / Pellegatta, Serena; Savoldo, Barbara; Di Ianni, Natalia; Corbetta, Cristina; Chen, Yuhui; Patané, Monica; Sun, Chuang; Pollo, Bianca; Ferrone, Soldano; DiMeco, Francesco; Finocchiaro, Gaetano; Dotti, Gianpietro.

In: Science Translational Medicine, Vol. 10, No. 430, eaao2731, 28.02.2018.

Research output: Contribution to journalArticle

Pellegatta, Serena ; Savoldo, Barbara ; Di Ianni, Natalia ; Corbetta, Cristina ; Chen, Yuhui ; Patané, Monica ; Sun, Chuang ; Pollo, Bianca ; Ferrone, Soldano ; DiMeco, Francesco ; Finocchiaro, Gaetano ; Dotti, Gianpietro. / Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres : Implications for CAR-T cell therapy. In: Science Translational Medicine. 2018 ; Vol. 10, No. 430.
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