Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses

被引：157
作者：
Zhang, Fanghui [1 ,2 ,3 ,4 ,5 ,6 ]
Li, Rongrong [1 ,2 ]
Yang, Yunshan [7 ]
Shi, Chunhui [8 ]
Shen, Yingying [1 ,2 ]
Lu, Chaojie [1 ,2 ]
Chen, Yinghu [9 ]
Zhou, Wu [10 ]
Lin, Aifu [11 ]
Yu, Lei [12 ]
Zhang, Wanjing [1 ,2 ]
Xue, Zhenwei [1 ,2 ]
Wang, Jianli [3 ,4 ,5 ,6 ]
Cai, Zhijian [1 ,2 ]
机构：
[1] Zhejiang Univ, Inst Immunol, Sch Med, Hangzhou 310009, Zhejiang, Peoples R China
[2] Zhejiang Univ, Dept Orthopaed, Affiliated Hosp 2, Sch Med, Hangzhou 310009, Zhejiang, Peoples R China
[3] Zhejiang Univ, Inst Immunol, Sch Med, Affiliated Hosp 1, Hangzhou 310058, Zhejiang, Peoples R China
[4] Zhejiang Univ, Bone Marrow Transplantat Ctr, Sch Med, Affiliated Hosp 1, Hangzhou 310058, Zhejiang, Peoples R China
[5] Zhejiang Univ, Inst Hematol, Hangzhou 310006, Zhejiang, Peoples R China
[6] Zhejiang Engn Lab Stem Cell & Immunotherapy, Hangzhou 310006, Zhejiang, Peoples R China
[7] Zhejiang Canc Hosp, Dept Chemotherapy, Hangzhou 310022, Zhejiang, Peoples R China
[8] Yuhuan Hosp Tradit Chinese Med, Dept Gynaecol & Obstet, Taizhou 317600, Peoples R China
[9] Zhejiang Univ, Childrens Hosp, Div Infect Dis, Zhejiang Key Lab Neonatal Dis,Sch Med, Hangzhou 310006, Zhejiang, Peoples R China
[10] Lishui Univ, Coll Med & Hlth, Dept Med, Lishui 323000, Peoples R China
[11] Zhejiang Univ, Coll Life Sci, Hangzhou 310058, Zhejiang, Peoples R China
[12] Zhejiang Univ, Sir Run Run Shaw Hosp, Lab Canc Biol, Key Lab Biotherapy Zhejiang,Med Sch, Hangzhou 310020, Zhejiang, Peoples R China
来源：
IMMUNITY | 2019年 / 50卷 / 03期
基金：
中国国家自然科学基金; 国家重点研发计划;
关键词：
ADENOSINE; CANCER; CD73; LYMPHOCYTES; GENERATION; PROTECTS; EXOSOMES; CD39;
D O I：
10.1016/j.immuni.2019.01.010
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19(+) extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8(+) T cell responses. Serum CD19(+) EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19+ EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1 alpha (HIF-1 alpha) promoted B cells to release CD19(+) EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1 alpha deficiency in B cells inhibited CD19(+) EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD Prkdc(scid) Il2rg(-/-) mice. Thus, decreasing CD19(+) EVs holds high potential to improve the chemotherapeutic antitumor effect.
引用
收藏
页码：738 / +
页数：20
相关论文
共 32 条
[1]   The Addition of Target Therapy to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Review [J].
Benevento, Ilaria ;
De Felice, Francesca ;
Musio, Daniela ;
Tombolini, Vincenzo .
CHEMOTHERAPY, 2017, 62 (05) :314-322
[2]   QUANTITATIVE RELATIONSHIPS BETWEEN CIRCULATING LEUKOCYTES AND INFECTION IN PATIENTS WITH ACUTE LEUKEMIA [J].
BODEY, GP ;
BUCKLEY, M ;
SATHE, YS ;
FREIREICH, EJ .
ANNALS OF INTERNAL MEDICINE, 1966, 64 (02) :328-+
[3]   Ecto-5-Nucleotidase on Immune Cells Protects From Adverse Cardiac Remodeling [J].
Boenner, Florian ;
Borg, Nadine ;
Jacoby, Christoph ;
Temme, Sebastian ;
Ding, Zhaoping ;
Floegel, Ulrich ;
Schrader, Juergen .
CIRCULATION RESEARCH, 2013, 113 (03) :301-312
[4]   Central and Effector Memory CD4 and CD8 T-Cell Responses to Tumor-Associated Antigens [J].
Caserta, Stefano ;
Borger, Jessica Geraldine ;
Zamoyska, Rose .
CRITICAL REVIEWS IN IMMUNOLOGY, 2012, 32 (02) :97-126
[5]   Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production [J].
Clayton, Aled ;
Al-Taei, Saly ;
Webber, Jason ;
Mason, Malcolm D. ;
Tabi, Zsuzsanna .
JOURNAL OF IMMUNOLOGY, 2011, 187 (02) :676-683
[6]   Functional polarization of tumour-associated macrophages by tumour-derived lactic acid [J].
Colegio, Oscar R. ;
Ngoc-Quynh Chu ;
Szabo, Alison L. ;
Chu, Thach ;
Rhebergen, Anne Marie ;
Jairam, Vikram ;
Cyrus, Nika ;
Brokowski, Carolyn E. ;
Eisenbarth, Stephanie C. ;
Phillips, Gillian M. ;
Cline, Gary W. ;
Phillips, Andrew J. ;
Medzhitov, Ruslan .
NATURE, 2014, 513 (7519) :559-+
[7]   Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression [J].
Deaglio, Silvia ;
Dwyer, Karen M. ;
Gao, Wenda ;
Friedman, David ;
Usheva, Anny ;
Erat, Anna ;
Chen, Jiang-Fan ;
Enjyoji, Keiichii ;
Linden, Joel ;
Oukka, Mohamed ;
Kuchroo, Vijay K. ;
Strom, Terry B. ;
Robson, Simon C. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (06) :1257-1265
[8]   Production of Adenosine by Ectonucleotidases: A Key Factor in Tumor Immunoescape [J].
Ghiringhelli, Francois ;
Bruchard, Melanie ;
Chalmin, Fanny ;
Rebe, Cedric .
JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY, 2012,
[9]   Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors [J].
Ghiringhelli, Francois ;
Apetoh, Lionel ;
Tesniere, Antoine ;
Aymeric, Laetitia ;
Ma, Yuting ;
Ortiz, Carla ;
Vermaelen, Karim ;
Panaretakis, Theocharis ;
Mignot, Gregoire ;
Ullrich, Evelyn ;
Perfettini, Jean-Luc ;
Schlemmer, Frederic ;
Tasdemir, Ezgi ;
Uhl, Martin ;
Genin, Pierre ;
Civas, Ahmet ;
Ryffel, Bernhard ;
Kanellopoulos, Jean ;
Tschopp, Juerg ;
Andre, Fabrice ;
Lidereau, Rosette ;
McLaughlin, Nicole M. ;
Haynes, Nicole M. ;
Smyth, Mark J. ;
Kroemer, Guido ;
Zitvogel, Laurence .
NATURE MEDICINE, 2009, 15 (10) :1170-U99
[10]   EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance [J].
Jiang, Lingling ;
Shen, Yingying ;
Guo, Danfeng ;
Yang, Diya ;
Liu, Jiajun ;
Fei, Xuefeng ;
Yang, Yunshan ;
Zhang, Buyi ;
Lin, Zhendong ;
Yang, Fei ;
Wang, Xiaojian ;
Wang, Keyi ;
Wang, Jianli ;
Cai, Zhijian .
NATURE COMMUNICATIONS, 2016, 7
1234