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TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

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Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEXTGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEXTGF-β1si. It was shown that LEXTGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEXTGF-β1si (DCLEX-TGF-β1si) more effectively promoted CD4+ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DCLEX-TGF-β1si inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DCLEX-TGF-β1si induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEXTGF-β1si may be used as a promising approach for leukemia immunotherapy.

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Abbreviations

CTL:

Cytotoxic T lymphocytes

DC:

Dendritic cells

DCLEX :

Dendritic cells pulsed with exosomes from non-manipulated L1210 cells

DCLEX-GFP :

Dendritic cells pulsed with exosomes from L1210 cells transfected with a control shRNA

DCLEX-TGF-β1si :

Dendritic cells pulsed with exosomes from the TGF-β1 silenced L1210 cells

HSP:

Heat shock protein

IFN-γ:

Interferon-γ

IL:

Interleukin

LEX:

Exosomes from non-manipulated L1210 cells

LEXGFP :

Exosomes from L1210 cells transfected with a control shRNA sequence

LEXTGF-β1si :

Exosomes from the TGF-β1-silenced L1210 cells

MRLs:

Minimal residual leukemia cells

NK:

Natural killer

TAA:

Tumor-associated antigens

TEX:

Tumor-derived exosome(s)

TGF-β1:

Transforming growth factor-β1

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Grant No. 81470314).

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Author notes

  1. Fang Huang and Jiangbo Wan have contributed equally.

Authors and Affiliations

  1. Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665# Kongjiang Road, Shanghai, 200090, China

    Fang Huang, Jiangbo Wan, Siguo Hao, Xiaohui Deng, Linjun Chen & Liyuan Ma

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  1. Fang Huang
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  2. Jiangbo Wan
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  3. Siguo Hao
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  4. Xiaohui Deng
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Correspondence to Siguo Hao.

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Huang, F., Wan, J., Hao, S. et al. TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model. Cancer Immunol Immunother 66, 1321–1331 (2017). https://doi.org/10.1007/s00262-017-2028-5

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  • DOI: https://doi.org/10.1007/s00262-017-2028-5

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