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 language | English |
|---|---|
| Article number | eaao2731 |
| Journal | Science Translational Medicine |
| Volume | 10 |
| Issue number | 430 |
| DOIs | |
| Publication status | Published - Feb 28 2018 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres
T2 - Implications for CAR-T cell therapy
AU - Pellegatta, Serena
AU - Savoldo, Barbara
AU - Di Ianni, Natalia
AU - Corbetta, Cristina
AU - Chen, Yuhui
AU - Patané, Monica
AU - Sun, Chuang
AU - Pollo, Bianca
AU - Ferrone, Soldano
AU - DiMeco, Francesco
AU - Finocchiaro, Gaetano
AU - Dotti, Gianpietro
PY - 2018/2/28
Y1 - 2018/2/28
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85042846306&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aao2731
DO - 10.1126/scitranslmed.aao2731
M3 - Article
VL - 10
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 430
M1 - eaao2731
ER -