Dual effect of DLBCL-derived EXOs in lymphoma to improve DC vaccine efficacy in vitro while favor tumorgenesis in vivo

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Abstract

Background

Exosomes derived from tumor cells (TEXs) are involved in both immune suppression, angiogenesis, metastasis and anticancer stimulatory, but the biological characteristics and role of diffuse large B cell lymphoma (DLBCL)-derived exosomes have been less investigated.

Methods

Exosomes (EXOs) were isolated from OCI-LY3, SU-DHL-16, and Raji cells and biological characteristics of EXOs were investigated using electron microscopy, flow cytometry analysis, and Western blot analysis. The protein expression of EXOs was determined by an antibody array. Next, the communication between EXOs and lymphoma cell, stromal cell, dendritic cells (DCs), and T cells was evaluated. Finally, effect of DLBCL TEXs on tumor growth in vivo was investigated.

Results

We demonstrated that EXOs derived from DLBCL cell lines displayed malignancy molecules such as c-Myc, Bcl-2, Mcl-1, CD19, and CD20. There was a different protein expression pattern between DLBCL TEXs and Burkitt lymphoma TEXs. DLBCL TEXs were easily captured by DCs and lymphoma cells, and mainly acted as an immunosuppressive mediator, evidenced by induction of apoptosis and upregulation of PD-1 in T cells. Furthermore, the TEXs stimulated not only cell proliferation, migration of stromal cells but also angiogenesis. As a result, the TEXs promoted tumor growth in vivo. On other hand, DLBCL TEXs did not induce apoptosis of DCs. After pulsed with the TEXs, DCs could stimulate clonal expansion of T cells, increase the secretion of IL-6 and TNFα, and decrease the production of immunosuppressive cytokine IL-4 and IL-10. The T cells from tumor bearing mice immunized by TEX were shown to possess superior antilymphoma potency relative to immunization of tumor lysates.

Conclusions

This study provides the framework for novel immunotherapies targeting TEXs in DLBCL.

Electronic supplementary material

The online version of this article (10.1186/s13046-018-0863-7) contains supplementary material, which is available to authorized users.

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Most cited references 33

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Critical Evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the Measurement of Nanoparticles and Protein Aggregates

Vasco Filipe, Andrea Hawe, Wim Jiskoot (2010)

Purpose To evaluate the nanoparticle tracking analysis (NTA) technique, compare it with dynamic light scattering (DLS) and test its performance in characterizing drug delivery nanoparticles and protein aggregates. Methods Standard polystyrene beads of sizes ranging from 60 to 1,000 nm and physical mixtures thereof were analyzed with NTA and DLS. The influence of different ratios of particle populations was tested. Drug delivery nanoparticles and protein aggregates were analyzed by NTA and DLS. Live monitoring of heat-induced protein aggregation was performed with NTA. Results NTA was shown to accurately analyze the size distribution of monodisperse and polydisperse samples. Sample visualization and individual particle tracking are features that enable a thorough size distribution analysis. The presence of small amounts of large (1,000 nm) particles generally does not compromise the accuracy of NTA measurements, and a broad range of population ratios can easily be detected and accurately sized. NTA proved to be suitable to characterize drug delivery nanoparticles and protein aggregates, complementing DLS. Live monitoring of heat-induced protein aggregation provides information about aggregation kinetics and size of submicron aggregates. Conclusion NTA is a powerful characterization technique that complements DLS and is particularly valuable for analyzing polydisperse nanosized particles and protein aggregates.

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Exosomes in cancer: small particle, big player

Xu Zhang, Xiao Shuai Yuan, Hui Shi … (2015)

Exosomes have emerged as a novel mode of intercellular communication. Exosomes can shuttle bioactive molecules including proteins, DNA, mRNA, as well as non-coding RNAs from one cell to another, leading to the exchange of genetic information and reprogramming of the recipient cells. Increasing evidence suggests that tumor cells release excessive amount of exosomes, which may influence tumor initiation, growth, progression, metastasis, and drug resistance. In addition, exosomes transfer message from tumor cells to immune cells and stromal cells, contributing to the escape from immune surveillance and the formation of tumor niche. In this review, we highlight the recent advances in the biology of exosomes as cancer communicasomes. We review the multifaceted roles of exosomes, the small secreted particles, in communicating with other cells within tumor microenvironment. Given that exosomes are cell type specific, stable, and accessible from body fluids, exosomes may provide promising biomarkers for cancer diagnosis and represent new targets for cancer therapy.

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Induction of Lymphocyte Apoptosis by Tumor Cell Secretion of FasL-bearing Microvesicles

Giovanna Andreola, Licia Rivoltini, Chiara Castelli … (2002)

The hypothesis that FasL expression by tumor cells may impair the in vivo efficacy of antitumor immune responses, through a mechanism known as ‘Fas tumor counterattack,’ has been recently questioned, becoming the object of an intense debate based on conflicting results. Here we definitely show that FasL is indeed detectable in the cytoplasm of melanoma cells and its expression is confined to multivesicular bodies that contain melanosomes. In these structures FasL colocalizes with both melanosomal (i.e., gp100) and lysosomal (i.e., CD63) antigens. Isolated melanosomes express FasL, as detected by Western blot and cytofluorimetry, and they can exert Fas-mediated apoptosis in Jurkat cells. We additionally show that melanosome-containing multivesicular bodies degranulate extracellularly and release FasL-bearing microvesicles, that coexpress both gp100 and CD63 and retain their functional activity in triggering Fas-dependent apoptosis of lymphoid cells. Hence our data provide evidence for a novel mechanism potentially operating in Fas tumor counterattack through the secretion of subcellular particles expressing functional FasL. Such vesicles may form a sort of front line hindering lymphocytes and other immunocompetent cells from entering neoplastic lesions and exert their antitumor activity.

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Author and article information

Contributors

Zhenzhen Chen: czzforget@zju.edu.cn

Liangshun You: youliangshun@zju.edu.cn

Lei Wang: b_brendel@hotmail.com

Xianbo Huang: huangxb888@zju.edu.cn

Hui Liu: sylen@zju.edu.cn

Ju ying Wei: weijuy@hotmail.com

Li Zhu: julia_474744804@aliyun.com

Wenbin Qian: 86-571-87235983 , qianwb@zju.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 13 August 2018

Publication date PMC-release: 13 August 2018

Publication date Collection: 2018

Volume: 37

Electronic Location Identifier: 190

Affiliations

[1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Hematology, the First Affiliated Hospital, College of Medicine, , Zhejiang University, ; Zhejiang, 310003 Hangzhou China

[2 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Malignant Lymphoma Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, , Zhejiang University, ; Zhejiang, 310003 Hangzhou China

[3 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Institute of Hematology, The First Affiliated Hospital, College of Medicine, , Zhejiang University, ; 79# Qingchun Road, Hangzhou, 310003 People’s Republic of China

Article

Publisher ID: 863

DOI: 10.1186/s13046-018-0863-7

PMC ID: 6090784

PubMed ID: 30103789

SO-VID: ffd33375-5fe3-417b-a7fc-3dd8067042bf

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 May 2018

Date accepted : 2 August 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81670178

Award ID: 81500110

Award ID: 81500111

Award Recipient : Liangshun You Lei Wang Wenbin Qian

Funded by: National Key Research and Development Program of China

Award ID: 2016YFC090150X

Award Recipient : Wenbin Qian

Funded by: Research Project for Practice Development of National TCM Clinical Research Bases

Award ID: JDZX2015113

Award Recipient : Wenbin Qian

Funded by: Natural Science Foundation of Zhejiang Province (CN)

Award ID: LY18H160008

Award Recipient : Hui Liu

Funded by: Funds of Science Technology Department of Zhejiang Province

Award ID: 2018C03016-1

Award Recipient : Wenbin Qian

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: exosome,diffuse large b-cell lymphoma,dendritic cells,cancer immunotherapy,immunomodulation,invasion,tumor microenvironment

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: exosome, diffuse large b-cell lymphoma, dendritic cells, cancer immunotherapy, immunomodulation, invasion, tumor microenvironment

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Dual effect of DLBCL-derived EXOs in lymphoma to improve DC vaccine efficacy in vitro while favor tumorgenesis in vivo

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Cancer Immunotherapy

Most cited references 33

Critical Evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the Measurement of Nanoparticles and Protein Aggregates

Exosomes in cancer: small particle, big player

Induction of Lymphocyte Apoptosis by Tumor Cell Secretion of FasL-bearing Microvesicles

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Cited by 39

Most referenced authors 1,054