Enhanced immunogenicity of leukemia-derived exosomes via transfection with lentiviral vectors encoding costimulatory mol
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ORIGINAL PAPER
Enhanced immunogenicity of leukemia-derived exosomes via transfection with lentiviral vectors encoding costimulatory molecules Weiwei Hu 1 & Fang Huang 1 & Liuxin Ning 1 & Jun Hao 2,3 & Jiangbo Wan 1 & Siguo Hao 1 Accepted: 15 May 2020 # The Author(s) 2020
Abstract Background: Tumor cell-derived exosomes (TEXs) have been widely used to induce antitumor immune responses in animal models and clinical trials. Similarly, leukemia cell-derived exosomes (LEXs) can induce antileukemia immune responses in animal models. However, the antileukemia immunity induced by LEXs is less effective, which may be due to an inadequate costimulatory capacity. Methods: In this study, we transduced L1210 leukemia cells with a lentiviral vector encoding two B7 costimulatory molecules (CD80, CD86) and obtained LEXs that highly expressed CD80 and CD86. The antileukemia immune response derived from these LEXs was examined in vitro and in vivo in animal models. Results: We found that B7 gene-modified LEXs, including LEX-CD80, LEX-CD86, and LEX-8086, could significantly boost the expression of CD80 and CD86 in dendritic cells (DCs) and promote the secretion of functional cytokines such as TNF-α and IL-12. Moreover, these B7 gene-modified LEXs, particularly LEX-CD8086, could effectively induce CD4+ T cell proliferation, Th1 cytokine secretion, and an antigen-specific anti-leukemia cytotoxic T lymphocyte (CTL) response. Additional animal studies indicated that immunization with B7 gene-modified LEXs, in particular LEX-CD8086, could significantly retard tumor growth compared to the control LEXnull group. Conclusions: This study sheds light on the feasibility of obtaining LEXs that overexpress costimulatory molecules via genetically modified leukemia cells, thereby enhancing their anti-leukemia immunity and providing a potential therapeutic strategy that contributes to leukemia immunotherapy. Keywords Leukemia . Exosomes . Costimulatory molecules . Immunotherapy
Abbreviations DC Dendritic cell TEX Tumor-derived exosome LEX Leukemia-derived exosome
HSP IL-2 TGF-β1 TNF-α IFN-γ CTL APC CTLA-4
Heat shock protein Interleukin 2 Transformation growth factor-1 Tumor necrosis factor-α Interferon-γ Cytotoxic T lymphocyte Antigen-presenting cell Cytotoxic T lymphocyte-associated protein 4
* Siguo Hao [email protected] 1
Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665# Kongjiang Road, Shanghai 200090, China
2
Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
3
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada
1 Introduction Recently, remarkable progresses have been made in the clinical treatment of leukemia, and these are mainly attributed to high doses of chemotherapy and hematopoietic stem cell transplantation [1, 2]. However, several patients, especially the elderly, still suffer and cannot benefit from these strategies [3]. Therefore, novel and tolerable treatments for l
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