Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells

Cancer Immunology Research - Tập 6 Số 9 - Trang 1057-1068 - 2018
Jingwei Ma1,2, Keke Wei2, Xiao‐Hui Zhang2, Ke Tang2, Fei Li1, Junwei Liu3, Pingwei Xu2, Yuandong Yu2, Weiwei Sun2, Liyan Zhu2, Jie Chen2, Li Zhou2, Xiaoyu Liang4, Jiadi Lv4, Roland Fiskesund4, Yuying Liu4, Bo Huang1,2,4
11Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
22Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
34Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
43Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.

Tóm tắt

Abstract Tumor cell–derived microparticles (T-MP) contain tumor antigen profiles as well as innate signals, endowing them with vaccine potential; however, the precise mechanism by which DCs present T-MP antigens to T cells remains unclear. Here, we show that T-MPs activate a lysosomal pathway that is required for DCs presenting tumor antigens of T-MPs. DCs endocytose T-MPs to lysosomes, where T-MPs increase lysosomal pH from 5.0 to a peak of 8.5 via NOX2-catalyzed reactive oxygen species (ROS) production. This increased pH, coupled with T-MP–driven lysosomal centripetal migration, promotes the formation of MHC class I–tumor antigen peptide complexes. Concurrently, endocytosis of T-MPs results in the upregulation of CD80 and CD86. T-MP–increased ROS activate lysosomal Ca2+ channel Mcoln2, leading to Ca2+ release. Released Ca2+ activates transcription factor EB (TFEB), a lysosomal master regulator that directly binds to CD80 and CD86 promoters, promoting gene expression. These findings elucidate a pathway through which DCs efficiently present tumor antigen from T-MPs to CD8+ T cells, potentiating T-MPs as a novel tumor cell–free vaccine with clinical applications. Cancer Immunol Res; 6(9); 1057–68. ©2018 AACR.

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