A Newly Developed TGF-Β-Responsive CAR T Cell for Enhanced Proliferation and Cytokine Secretion

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for cancer treatment.
• Solid tumors present challenges to CAR T cell efficacy due to the immunosuppressive tumor microenvironment (TME).
• Tumor growth factor-beta (TGF-β) is a key immunosuppressive cytokine in the TME, hindering CAR T cell function.

Purpose of the Study:

• To investigate the efficacy of TGF-β receptor II (TGF-βRII) CAR T cells in overcoming TGF-β-mediated immunosuppression.
• To assess the functionality of engineered CAR T cells in TGF-β-rich environments.

Main Methods:

• Development of novel TGF-βRII CAR T cells and dominant-negative TGF-β receptor (dnTβRII) T cells using Jurkat cells.
• Confirmation of transduction efficiency and surface receptor expression via flow cytometry.
• Assessment of T cell activation (CD69), proliferation (Ki-67), and cytokine secretion (IL-2, IFN-γ) using ELISA.

Main Results:

• Successful surface expression of TGF-βRII CAR (62%) and dnTβRII (24%) was confirmed.
• TGF-βRII CAR T cells exhibited dose-dependent activation and enhanced proliferation (up to 96% Ki-67+) in the presence of TGF-β.
• Significant increases in IL-2 and IFN-γ secretion were observed in TGF-βRII CAR T cells, while dnTβRII T cells showed limited sustained function.

Conclusions:

• TGF-βRII CAR T cells effectively resist TGF-β-mediated suppression in solid tumor environments.
• Engineered CAR T cells promote activation, proliferation, and cytokine release, demonstrating potential for improved cancer therapy.
• This approach offers a promising strategy to overcome TGF-β-driven immunosuppression and enhance CAR T cell therapy efficacy.