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Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

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Abstract

Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested damage-associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines.

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Abbreviations

Bax:

Bcl-2–associated X protein

Bcl-2:

B-cell lymphoma 2

CRT:

Calreticulin

DAMPs:

Damage-associated molecular patterns

DC:

Dendritic cell

DX:

Doxorubicin

DX-TCL:

Doxorubicin-treated tumor cells as cell lysates

ER:

Endoplasmic reticulum

GM-CSF:

Granulocyte/macrophage-colony stimulatory factor

GRP:

Glucose-related protein

HMGB1:

High-mobility group protein box 1

HSP:

Heat shock protein

MHC:

Major histocompatibility complex

MG:

MG-132

MG-TCL:

MG-132-treated tumor cells as cell lysates

RORγt:

Retinoic acid receptor-related orphan nuclear receptor gamma t

SK:

Shikonin

SK-TCL:

Shikonin-treated tumor cells as cell lysates

Tbet:

Th1-specific T box transcription factor

TCL:

Tumor cell lysate

TLR4:

Toll-like receptor 4

TNFα:

Tumor necrosis factor alpha

TX:

Paclitaxel

TX-TCL:

Paclitaxel-treated tumor cells as cell lysates

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgments

This present work was sponsored by the Grant (NSC-097-2320-B-001-012) from the National Science Council, Taiwan and the Grant (99-Academia Sinica Investigator Award-12) from Academia Sinica, Taiwan. We thank Heiko Kuhn, Miranda Jane Loney, and Ruth Giodan for manuscript editing.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC

    Hui-Ming Chen & Wen-Chin Yang

  2. Institute of Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Academia Sinica Rd. Sec. 2, Nankang District, Taipei, 11529, Taiwan, ROC

    Hui-Ming Chen, Pi-Hsueh Wang, Swey-Shen Chen, Chih-Chun Wen, Yun-Hsiang Chen, Wen-Chin Yang & Ning-Sun Yang

  3. Institute of Biotechnology, National Taiwan University, Taipei, Taiwan, ROC

    Ning-Sun Yang

  4. Department of Life Sciences, National Central University, Zhongli, Taiwan, ROC

    Ning-Sun Yang

  5. Department of Allergy and Vaccinology, IGE Therapeutics, Inc., San Diego, CA, 92131, USA

    Swey-Shen Chen

  6. Department of Molecular Biology, The Scripps Research Institute, San Diego, CA, 92037, USA

    Swey-Shen Chen

  7. Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC

    Ning-Sun Yang

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  1. Hui-Ming Chen
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Chen, HM., Wang, PH., Chen, SS. et al. Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol Immunother 61, 1989–2002 (2012). https://doi.org/10.1007/s00262-012-1258-9

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