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Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Cholangiocarcinoma (CCA) is a cancer of the bile ducts that is associated with poor prognosis and poor treatment outcome. Approximately one-third of CCA patients can undergo surgery, but the recurrence rate is high and chemotherapy often cannot satisfactorily prolong survival. Cellular immunotherapy based on adoptive T-cell transfer is a potential treatment for CCA; however, the development of this technology and the search for an appropriate tumor-associated antigen are still ongoing. To enhance the cytotoxic activity of effector T cells against CCA, we developed self-differentiated monocyte-derived dendritic cells (SD-DC) presenting cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A), which is an overexpressed protein that plays a role in the regulation of tumor growth to activate T cells for CCA cell killing. Dendritic cells (DCs) transduced with lentivirus harboring tri-cistronic cDNA sequences (SD-DC-PR) could produce granulocyte–macrophage colony-stimulating factor, interleukin-4, and PRKAR1A. SD-DC showed similar phenotypes to those of DCs derived by conventional method. Autologous effector T cells (CD3+, CD8+) activated by SD-DC-PR exhibited greater cytotoxic activity against CCA than those activated by conventionally-derived DCs. Effector T cells activated by SD-DC-PR killed 60% of CCA cells at an effector-to-target ratio of 15:1, which is approximately twofold greater than the cell killing performance of those stimulated with control DC. The cytotoxic activities of effector T cells activated by SD-DC-PR against CCA cells were significantly associated with the expression levels of PRKR1A in CCA cells. This finding that SD-DC-PR effectively stimulated autologous effector T cells to kill CCA cells may help to accelerate the development of novel therapies for treating CCA.

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Abbreviations

CCA:

Cholangiocarcinoma

CHX:

Cycloheximide

CTA:

Cancer–testis antigens

DAB:

Diaminobenzidine

FOXM1:

Forkhead box M1

MAGE:

Melanoma-associated antigen

PBMC:

Peripheral blood mononuclear cell

PI:

Propidium iodide

PRKAR1A:

cAMP-dependent protein kinase type I-alpha regulatory subunit

SD-DC:

Self-differentiated monocyte-derived dendritic cell

TAA:

Tumor-associated antigen

TRP2:

Tyrosinase-related protein 2

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Acknowledgements

The authors gratefully acknowledge Dr. Naravat Poungvarin of the Clinical Molecular Pathology Laboratory, Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand for providing lentivirus vectors. The authors also thank Kevin Jone for editing.

Funding

This work was financially supported by Mahidol University (Grant no. R016010006), the Thailand Research Fund (TRF) (Grant no. IRG5980006), the TRF-International Research Network (TRF-IRN) (Grant no. IRN58W001), and the Newton Fund-Office of Higher Education Commission (OHEC) Institutional Links Grant. Chutamas Thepmalee was supported by a TRF-Royal Golden Jubilee (TRF-RGJ)-Ph.D. Scholarship (Scholarship no. PHD/0044/2556). Nattaporn Phanthaphol was supported by a TRF-IRN Scholarship (Scholarship no. IRN5801PHDW03). Mutita Junking was supported by a TRF Grant for New Researcher (Grant no. TRG5780173) and a Siriraj Chalermprakiat Grant. Pa-thai Yenchitsomanus was supported by a Siriraj Chalermprakiat Grant.

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Authors and Affiliations

  1. Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand

    Aussara Panya

  2. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand

    Aussara Panya, Chutamas Thepmalee, Nunghathai Sawasdee, Jatuporn Sujjitjoon, Nattaporn Phanthaphol, Mutita Junking & Pa-thai Yenchitsomanus

  3. Center of Excellence in Bioresources for Agriculture, Industry and Medicine, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand

    Aussara Panya

  4. Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Chutamas Thepmalee & Nattaporn Phanthaphol

  5. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Sopit Wongkham

  6. Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Sopit Wongkham

Authors
  1. Aussara Panya
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  2. Chutamas Thepmalee
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  3. Nunghathai Sawasdee
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  4. Jatuporn Sujjitjoon
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  5. Nattaporn Phanthaphol
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  6. Mutita Junking
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  7. Sopit Wongkham
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  8. Pa-thai Yenchitsomanus
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Contributions

AP conceived the study, designed and conducted experiments, and drafted and revised the manuscript. CT optimized DC culture protocol and conducted experiments. NS designed and conducted experiments. JS designed and conducted experiments. NP conducted experiments. MJ developed and optimized DC culture protocol, and conducted experiments. SW acquired human CCA tissues, and isolated and cultured CCA cells. PY conceived the study, managed the research team, designed experiments, and edited and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Pa-thai Yenchitsomanus.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval and ethical standards

For the use of human tissues from cancer patients, written informed consent was obtained in accordance with the approval of the Human Research Committee, Khon Kaen University (Approval number: #HE471214). For the use of blood samples from healthy donors, written informed consent was obtained in accordance with the approval of the Siriraj Institutional Review Board (SIRB), Faculty of Medicine Siriraj Hospital, Mahidol University (Approval number: Si 517/2016).

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Panya, A., Thepmalee, C., Sawasdee, N. et al. Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells. Cancer Immunol Immunother 67, 1579–1588 (2018). https://doi.org/10.1007/s00262-018-2212-2

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  • DOI: https://doi.org/10.1007/s00262-018-2212-2

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