期刊
BRITISH JOURNAL OF CANCER
卷 127, 期 12, 页码 2175-2185出版社
SPRINGERNATURE
DOI: 10.1038/s41416-022-02013-z
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资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [499549016]
This study demonstrates the impact of selective adenosine A2(A) and A2(B) receptor antagonist AB928 on CAR T cell function, showing that AB928 treatment enhances cytokine secretion, proliferation, and cytotoxicity of CAR T cells, leading to improved in vivo activation.
Background Chimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response. Methods Here, we present the impact of the selective adenosine A2(A) and A2(B) receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma. Results We found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo. Conclusions Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.
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