Kiểm Soát Biểu Hiện PD-L1 Bằng Sự Kích Hoạt Oncogenic Của Đường Phụ Trạng AKT–mTOR Trong Ung Thư Phổi Không Nhỏ
Tóm tắt
Những biến đổi trong EGFR, KRAS và ALK là những yếu tố thúc đẩy ung thư trong ung thư phổi, nhưng cách mà tín hiệu oncogenic ảnh hưởng đến miễn dịch trong môi trường vi mô khối u mới chỉ bắt đầu được hiểu biết. Sự ức chế miễn dịch có thể đóng góp vào bệnh ung thư phổi, vì các thuốc ức chế điểm kiểm soát miễn dịch như PD-1 và PD-L1 có lợi ích lâm sàng. Ở đây, chúng tôi chỉ ra rằng sự kích hoạt của đường mòn AKT–mTOR điều chỉnh chặt chẽ biểu hiện PD-L1 cả trong ống nghiệm và trong mô hình in vivo. Cả sự kích thích oncogenic và sự kích thích do IFNγ gây ra đối với PD-L1 đều phụ thuộc vào mTOR. Ở các khối u biểu mô phổi adenocarcinoma và carcinoma tế bào vảy ở người, biểu hiện PD-L1 trên màng đã được liên kết đáng kể với sự kích hoạt mTOR. Những dữ liệu này gợi ý rằng sự kích hoạt oncogenic của đường mòn AKT–mTOR thúc đẩy việc thoát khỏi miễn dịch bằng cách điều khiển biểu hiện PD-L1, điều này đã được xác nhận trong các mô hình chuột đồng sinh và chuột được kỹ thuật di truyền trong ung thư phổi, trong đó một chất ức chế mTOR kết hợp với kháng thể PD-1 đã giảm sự phát triển khối u, tăng cường các tế bào T xâm nhập vào khối u và giảm tế bào T điều hòa. Cancer Res; 76(2); 227–38. ©2015 AACR.
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