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

Fanghui Zhang; Rongrong Li; Yunshan Yang; Chunhui Shi; Yingying Shen; Chaojie Lu; Yinghu Chen; Wu Zhou; Aifu Lin; Lei Yu; Wanjing Zhang; Zhenwei Xue; Jianli Wang; Zhijian Cai

doi:10.1016/j.immuni.2019.01.010

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

Immunity. 2019 Mar 19;50(3):738-750.e7. doi: 10.1016/j.immuni.2019.01.010. Epub 2019 Feb 12.

Authors

Fanghui Zhang¹, Rongrong Li², Yunshan Yang³, Chunhui Shi⁴, Yingying Shen², Chaojie Lu², Yinghu Chen⁵, Wu Zhou⁶, Aifu Lin⁷, Lei Yu⁸, Wanjing Zhang², Zhenwei Xue², Jianli Wang⁹, Zhijian Cai¹⁰

Affiliations

¹ Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, China.
² Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
³ Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou 310022, China.
⁴ Department of Gynaecology and Obstetrics, Yuhuan Hospital of Traditional Chinese Medicine, Taizhou 317600, China.
⁵ Division of Infection Disease, Zhejiang Key Laboratory for Neonatal Diseases, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
⁶ Department of Medicine, College of Medicine and Health, Lishui University, Lishui 323000, China.
⁷ College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
⁸ Laboratory of Cancer Biology, The Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310020, China.
⁹ Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, China. Electronic address: jlwang@zju.edu.cn.
¹⁰ Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: caizj@zju.edu.cn.

PMID: 30770248
DOI: 10.1016/j.immuni.2019.01.010

Abstract

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-1α (HIF-1α) promoted B cells to release CD19⁺ EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1α 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^scidIl2rg^-/- mice. Thus, decreasing CD19⁺ EVs holds high potential to improve the chemotherapeutic antitumor effect.

Keywords: B cells; CD19; CD39; CD73; HIF-1α; Rab27a; cancer; chemotherapy; extracellular vesicles.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD19 / immunology
B-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / immunology*
Cell Line
Cell Line, Tumor
Extracellular Vesicles / immunology*
Female
HEK293 Cells
Herpesvirus 4, Human / immunology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / immunology
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
NIH 3T3 Cells
RNA, Messenger / immunology
Transcription, Genetic / immunology
rab27 GTP-Binding Proteins / immunology

Substances

Antigens, CD19
Hypoxia-Inducible Factor 1, alpha Subunit
RNA, Messenger
rab27 GTP-Binding Proteins