Inhibitor deacetylase histone AR-42 tăng cường miễn dịch chống khối u trung gian CD8+ T tế bào đặc hiệu E7 được kích thích bởi tiêm chủng DNA HPV điều trị

Springer Science and Business Media LLC - Tập 91 - Trang 1221-1231 - 2013
Sung Yong Lee1,2, Zhuomin Huang1,3, Tae Heung Kang1,4, Ruey-Shyang Soong1,5,6, Jayne Knoff1, Ellen Axenfeld1, Chenguang Wang7, Ronald D. Alvarez8, Ching-Shih Chen9, Chien-Fu Hung1,10, T.-C. Wu1,11,12,10,13
1Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, USA
2Department of Internal Medicine, Korea University Medical Center, Seoul, South Korea
3Department of Gynecology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China
4Department of Immunology, College of Medicine, Konkuk University, Chungju, Republic of Korea
5Department of General Surgery, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
6Chang Gung University College of Medicine, Taoyuan, Taiwan
7Department of Biostatistics and Bioinformatics, Sidney Kimmel Cancer Comprehensive Cancer Center Johns Hopkins University, Baltimore, USA
8Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, USA
9Division of Medical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, USA
10Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, USA
11Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, USA
12Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, USA
13Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, USA

Tóm tắt

Chúng tôi đã tạo ra một loại vắc xin DNA mạnh mẽ mã hóa calreticulin liên kết với protein gây ung thư E7 của virus HPV (CRT/E7). Trong khi điều trị bằng vắc xin DNA CRT/E7 tạo ra phản ứng miễn dịch đặc hiệu với khối u đáng kể ở chuột đã tiêm chủng, độ mạnh của vắc xin DNA có thể cải thiện hơn nữa bằng cách đồng quản lý với một chất ức chế deacetylase histone (HDACi) vì HDACi đã được chứng minh là làm tăng biểu hiện của các phân tử MHC lớp I và II. Do đó, chúng tôi nhằm xác định xem việc đồng quản lý một HDACi mới, AR-42, với vắc xin DNA HPV điều trị có thể cải thiện việc kích hoạt các tế bào T CD8+ đặc hiệu với kháng nguyên HPV, từ đó dẫn đến hiệu ứng điều trị khối u mạnh mẽ hay không. Để thực hiện điều này, chuột TC-1 mang khối u biểu hiện E7 của HPV-16 được điều trị bằng đường uống AR-42 và/hoặc vắc xin DNA CRT/E7 thông qua súng gen. Chuột được theo dõi các phản ứng miễn dịch tế bào T CD8+ đặc hiệu với E7 và hiệu ứng chống khối u. Các chuột mang khối u TC-1 được điều trị bằng AR-42 và vắc xin DNA CRT/E7 sống sót lâu hơn, tăng trưởng khối u giảm và phản ứng miễn dịch đặc hiệu E7 được cải thiện so với chuột chỉ điều trị bằng AR-42 hoặc vắc xin DNA CRT/E7 đơn độc. Bên cạnh đó, việc điều trị các tế bào TC-1 bằng AR-42 làm tăng sự biểu hiện bề mặt của các phân tử MHC lớp I và tăng tính nhạy cảm của các tế bào khối u đối với khả năng diệt tế bào của các tế bào T đặc hiệu E7. Nghiên cứu này chỉ ra khả năng của AR-42 trong việc nâng cao đáng kể độ mạnh của vắc xin DNA CRT/E7 bằng cách cải thiện phản ứng miễn dịch đặc hiệu với khối u và các hiệu ứng chống khối u. Cả hai loại vắc xin DNA AR-42 và CRT/E7 đã được sử dụng trong các thử nghiệm lâm sàng độc lập; nghiên cứu hiện tại làm cơ sở cho các thử nghiệm lâm sàng trong tương lai kết hợp cả hai phương pháp điều trị trong liệu pháp ung thư cổ tử cung.

Từ khóa

#HDACi #vắc xin DNA HPV #miễn dịch chống khối u #CD8+ T tế bào #ung thư cổ tử cung

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