Research ArticleCancer

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

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Science Translational Medicine  28 Feb 2018:
Vol. 10, Issue 430, eaao2731
DOI: 10.1126/scitranslmed.aao2731

A CAR to drive out glioblastoma

T cells with chimeric antigen receptors (CARs) targeting individual tumor antigens can be a very effective form of immunotherapy, but they only work when tumor cells express the target antigens. This presents a problem for tumors like glioblastoma, where the expression of potential targets is generally heterogeneous. However, Pellegatta et al. have identified a protein called chondroitin sulfate proteoglycan 4 (CSPG4), which is present on 67% of glioblastomas and induced by glial cells surrounding the tumor. The authors showed that targeting CSPG4 with CAR-T cells effectively treats glioblastoma in mouse models, with no evidence of antigen loss resulting in tumor escape.

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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