Journal
ONCOIMMUNOLOGY
Volume 9, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2020.1824643
Keywords
CAR-T cell; solid tumor; A2AR; CRISPR
Categories
Funding
- National Key Research and Development Program of China [2018YFA0107703, 2019YFA0110000]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16010503]
- National Natural Science Foundation of China [81773269]
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Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CAR-T cells, its effect on human CAR-T cells has not been fully elucidated. In particular, there was no evaluation of the CAR-T cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CAR-T cells, and only A2AR was responsible for adenosine-induced impairment of CAR-T cell function. DisruptingA2ARgene in human CAR-T cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CAR-T cellsin vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy ofA2ARknock-out CAR-T cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate thatA2ARknock-out CAR-T cells have the potential of being an improved CAR-T cell therapy in treating solid tumors.
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