Modified dendritic cell-derived exosomes activate both NK cells and T cells through the NKG2D/NKG2D-L pathway to kill CML cells with or without T315I mutation

作者全名："Du, Zhuanyun; Huang, Zhenglan; Chen, Xi; Jiang, Guoyun; Peng, Yuhang; Feng, Wenli; Huang, Ningshu"

作者地址："[Du, Zhuanyun; Huang, Zhenglan; Jiang, Guoyun; Peng, Yuhang; Feng, Wenli] Chongqing Med Univ, Sch Lab Med, Dept Clin Hematol, Key Lab Lab Med Diagnost,Minist Educ, 1,Yixueyuan Rd, Chongqing 400016, Peoples R China; [Chen, Xi] Chongqing Med Univ, Ctr Clin Mol Med, Minist Educ, Key Lab Child Dev & Disorders,Natl Clin Res Ctr C, Chongqing, Peoples R China; [Huang, Ningshu] Chongqing Med Univ, Childrens Hosp, China Int Sci & Technol Cooperat Base Child Dev &, Natl Clin Res Ctr Child Hlth & Disorders,Dept Cli, Chongqing, Peoples R China"

通信作者："Feng, WL (通讯作者)，Chongqing Med Univ, Sch Lab Med, Dept Clin Hematol, Key Lab Lab Med Diagnost,Minist Educ, 1,Yixueyuan Rd, Chongqing 400016, Peoples R China.; Huang, NS (通讯作者)，Chongqing Med Univ, Childrens Hosp, China Int Sci & Technol Cooperat Base Child Dev &, Natl Clin Res Ctr Child Hlth & Disorders,Dept Cli, Chongqing, Peoples R China."

来源：EXPERIMENTAL HEMATOLOGY & ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000807530000001

JCR分区：Q1

影响因子：10.9

年份：2022

卷号：11

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Chronic myeloid leukemia; Dendritic cell-derived exosomes; RAE-1 gamma; T cells; NK cells

摘要："Background: Tyrosine kinase inhibitors have achieved quite spectacular advances in the treatment of chronic myeloid leukemia (CML), but disease progression and drug resistance that related to the T315I mutation, remain major obstacles. Dendritic cell-derived exosomes (Dex) induce NK cell immunity, but have yet to achieve satisfactory clinical efficacy. An approach to potentiate antitumor immunity by inducing both NK- and T-cell activation is urgently needed. Retinoic acid early inducible-1 gamma (RAE-1 gamma), a major ligand of natural killer group 2 member D (NKG2D), plays an important role in NK-cell and T-lymphocyte responses. We generated RAE-1 gamma enriched CML-specific Dex (CML-RAE-1 gamma-Dex) from dendritic cells (DCs) pulsed with lysates of RAE-1 gamma-expressing CML cells or T315I-mutant CML cells, aiming to simultaneously activate NK cells and T lymphocytes. Methods: We generated novel CML-RAE-1 gamma-Dex vaccines, which expressed RAE-1 gamma, and were loaded with CML tumor cell lysates. NK cells or T lymphocytes were coincubated with CML-RAE-1 gamma-Dex vaccines. Flow cytometry was performed to evaluate the activation and proliferation of these immune cells. Cytokine production and cytotoxicity toward CML cells with or without the T315I mutation were detected by ELISPOT, ELISA and LDH assays. CML models induced by BCR-ABL or BCR-ABL(T315I) were used to determine the immunological function of Dex in vivo. Results: Herein, CML-RAE-1 gamma-Dex were prepared. CML-RAE-1 gamma-Dex effectively enhanced the proliferation and effector functions of NK cells, CD4(+) T cells and CD8(+) T cells, which in turn produced strong anti-CML efficacy in vitro. Moreover, CML-RAE-1 gamma-Dex-based immunotherapy inhibited leukemogenesis and generated durable immunological memory in CML mouse models. Similar immune responses were also observed with imatinib-resistant CML cells carrying the T315I mutation. Conclusions: This approach based on CML-RAE-1 gamma-Dex vaccines may be a promising strategy for CML treatment, especially for cases with the T315I mutation."

基金机构：National Natural Science Foundation of China [81902127]

基金资助正文：Our work was supported by the National Natural Science Foundation of China (Grant Nos. 81902127).