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Intrinsic ADRB2 inhibition improves CAR-T cell therapy efficacy against prostate cancer
Iqra Ajmal1, Muhammad Asad Farooq1, Yixin Duan1
1Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Abstract:
Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in patients with solid tumors. Recent in vitro and in vivo data have shown that adrenoceptor beta-2 (ADRB2) is a novel checkpoint receptor that inhibits T cell-mediated anti-tumor responses. To inhibit ADRB2-mediated inhibitory signaling, we downregulated ADRB2 in CAR-T (shβ2-CAR-T) cells via RNA interference, assessed different parameters, and compared them with conventional second-generation CAR-T cells. ADRB2 knockdown CAR-T cells exhibited enhanced cytotoxicity against prostate cancer cell lines in vitro, by increasing CD69, CD107a, GzmB, IFN-γ, T-bet, and GLUT-1. In addition, ADRB2 deficiency led to improved proliferation, increased CD8/CD4 T cell ratio, and decreased apoptosis in CAR-T cells. shβ2-CAR-T cells expressed more Bcl-2 and led to the generation of more significant proportions of T central memory cells. Finally, the ZAP-70/NF-κB signaling axis was shown to be responsible for the improved functions of novel CAR-T cells. In tumor-bearing mice, shβ2-CAR-T cells performed better than conventional CAR-T cells in eradicating prostate tumors. The study provides the basis for future clinical and translational CAR-T cell research to focus on adrenergic stress-mediated challenges in the tumor microenvironment of stressed tumors.
Insights
Researchers enhanced chimeric antigen receptor (CAR)-T cell therapy by downregulating adrenoceptor beta-2 (ADRB2) in T cells. This modification improved anti-tumor activity against solid tumors, offering a promising new strategy for cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR)-T cell therapy shows limited efficacy in solid tumors.
- Adrenoceptor beta-2 (ADRB2) acts as a novel checkpoint receptor inhibiting T cell anti-tumor responses.
- Targeting adrenergic signaling in the tumor microenvironment is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the role of ADRB2 in CAR-T cell function.
- To develop enhanced CAR-T cells by downregulating ADRB2 (shβ2-CAR-T).
- To evaluate the efficacy of shβ2-CAR-T cells against prostate cancer.
Main Methods:
- RNA interference was used to downregulate ADRB2 in CAR-T cells.
- In vitro assays assessed CAR-T cell cytotoxicity, proliferation, apoptosis, and immune marker expression.
- In vivo studies in tumor-bearing mice compared shβ2-CAR-T cells with conventional CAR-T cells.
Main Results:
- ADRB2 knockdown CAR-T cells demonstrated enhanced cytotoxicity and effector functions (increased CD69, CD107a, GzmB, IFN-γ, T-bet, GLUT-1).
- ADRB2 deficiency improved CAR-T cell proliferation, increased CD8/CD4 T cell ratio, reduced apoptosis, and promoted central memory cell generation.
- shβ2-CAR-T cells showed superior tumor eradication in vivo compared to conventional CAR-T cells.
- The ZAP-70/NF-κB signaling pathway was identified as crucial for the enhanced functions.
Conclusions:
- Downregulation of ADRB2 significantly enhances CAR-T cell anti-tumor activity against solid tumors.
- Targeting ADRB2 represents a novel approach to overcome T cell exhaustion in the tumor microenvironment.
- This strategy holds potential for future clinical applications in CAR-T cell therapy for cancer.
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