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Sci Transl Med. 2018 Feb 28;10(430). pii: eaao2731. doi: 10.1126/scitranslmed.aao2731.

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

Author information

1
Unit of Molecular Neuro-Oncology, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico C. Besta, Milan 20133, Italy.
2
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA.
4
Unit of Neuropathology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan 20133, Italy.
5
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Department of Neuro-Surgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan 20133, Italy.
7
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. gdotti@med.unc.edu.
8
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.

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-α (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.

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