Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 67, Issue 10, Pages 1579-1588Publisher
SPRINGER
DOI: 10.1007/s00262-018-2212-2
Keywords
Cholangiocarcinoma; Cellular immunotherapy; Dendritic cells; Self-differentiated monocyte-derived dendritic cells; Cytotoxic T cells
Categories
Funding
- Mahidol University [R016010006]
- Thailand Research Fund (TRF) [IRG5980006]
- TRF-International Research Network (TRF-IRN) [IRN58W001]
- Newton Fund-Office of Higher Education Commission (OHEC) Institutional Links Grant
- TRF-Royal Golden Jubilee (TRF-RGJ)-Ph.D. Scholarship [PHD/0044/2556]
- TRF-IRN Scholarship [IRN5801PHDW03]
- TRF Grant for New Researcher [TRG5780173]
- Siriraj Chalermprakiat Grant
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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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