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.
|Titolo:||Constitutive and TNF alpha-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy|
|Parole Chiave:||Chimeric antigen receptor; tumor-necrosis-factor; stem-cells; adjuvant temozolomide; molecular-cloning; NG2 proteoglycan; human glioma; in-vivo; caner; survival|
|Settore Scientifico Disciplinare:||Settore MED/27 - Neurochirurgia|
|Data di pubblicazione:||28-feb-2018|
|Digital Object Identifier (DOI):||10.1126/scitranslmed.aao2731|
|Appare nelle tipologie:||01 - Articolo su periodico|