Xóa bỏ thụ thể adenosine A2A trung gian CRISPR/Cas9 làm tăng cường hiệu quả của tế bào T CAR
Tóm tắt
Adenosine là một yếu tố ức chế miễn dịch làm hạn chế miễn dịch chống khối u thông qua việc ức chế nhiều tập hợp miễn dịch bao gồm cả tế bào T thông qua việc kích hoạt thụ thể adenosine A2A (A2AR). Sử dụng cả tế bào T CAR của chuột và người, chúng tôi cho thấy việc nhắm mục tiêu A2AR bằng một chiến lược CRISPR/Cas9 có liên quan đến lâm sàng làm tăng đáng kể hiệu quả in vivo của chúng, dẫn đến việc cải thiện sự sống sót của chuột. Các tác động do sự xóa gen A2AR trung gian qua CRISPR/Cas9 tạo ra mạnh mẽ hơn so với việc giảm dung lượng trung gian shRNA hoặc sự chặn dược lý của A2AR. Về mặt cơ chế, tế bào T CAR chỉnh sửa A2AR ở người cho thấy kháng cự đáng kể với những thay đổi phiên mã trung gian bởi adenosine, dẫn đến sản xuất gia tăng các cytokine bao gồm IFNγ và TNF, và tăng cường biểu hiện các gen liên quan đến con đường tín hiệu JAK-STAT. Tế bào T CAR thiếu A2AR được dung nạp tốt và không gây ra các bệnh lý rõ rệt ở chuột, hỗ trợ việc sử dụng CRISPR/Cas9 để nhắm mục tiêu A2AR nhằm cải thiện chức năng tế bào T CAR trong lâm sàng.
Từ khóa
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