TGF-β Blockade With SB525334 Enhances B7-H3 CAR-γδT Cell Efficacy Against Glioblastoma

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Transforming growth factor-beta (TGF-β) signaling drives glioblastoma (GBM) immunosuppression and therapy resistance.
• CAR-γδT cell therapy shows promise in hematologic cancers but faces challenges in solid tumors like GBM due to the immunosuppressive tumor microenvironment and T-cell exhaustion.
• TGFB1 upregulation in GBM correlates with poor prognosis, identifying TGF-β as a key resistance mediator.

Purpose of the Study:

• To evaluate if SB525334, a selective TGF-β receptor inhibitor, can improve the efficacy and persistence of CAR-γδT cells in GBM.
• To investigate the potential of combining TGF-β inhibition with CAR-γδT cell therapy to overcome immunosuppressive barriers in GBM.

Main Methods:

• Utilized bioinformatics to analyze TGFB1 expression in GBM.
• Assessed the impact of SB525334 on CAR-γδT cell function, antitumour efficacy, and the tumor microenvironment in GBM models.
• Compared combination therapy (SB525334 + CAR-γδT cells) with CAR-γδT cell therapy alone.

Main Results:

• SB525334 enhanced CAR-γδT cell function and antitumour efficacy by reducing TGF-β-mediated immunosuppression and T-cell exhaustion.
• Combination treatment significantly reduced GBM cell viability (40%-50% residual) compared to CAR-γδT therapy alone (70%-85%).
• SB525334 sustained CAR-γδT cell proliferation and effector function, remodeled the immunosuppressive tumor microenvironment, and promoted a pro-inflammatory immune signature.

Conclusions:

• SB525334 effectively enhances CAR-γδT cell therapy for GBM by counteracting TGF-β-driven immunosuppression.
• The combination strategy demonstrates synergistic antitumour effects and overcomes key limitations of CAR-γδT therapy in solid tumors.
• TGF-β1 small-molecule inhibitors represent a potential adjuvant to expand the clinical application of CAR-γδT cell immunotherapy for solid tumors.