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.

Pellegatta, S., Savoldo, B., Di Ianni, N., Corbetta, C., Chen, Y., Patané, M., et al. (2018). Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy. SCIENCE TRANSLATIONAL MEDICINE, 10(430) [10.1126/scitranslmed.aao2731].

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

Pellegatta, Serena
Primo
;
Corbetta, Cristina;Patané, Monica;
2018

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.
Articolo in rivista - Articolo scientifico
Immunotherapy, cancer, glioblastoma, CSPG4
English
2018
10
430
eaao2731
none
Pellegatta, S., Savoldo, B., Di Ianni, N., Corbetta, C., Chen, Y., Patané, M., et al. (2018). Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy. SCIENCE TRANSLATIONAL MEDICINE, 10(430) [10.1126/scitranslmed.aao2731].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/189083
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