Pan, Yi-RuYi-RuPanWu, Chiao-EnChiao-EnWuHuang, Wen-KuanWen-KuanHuangChen, Ming-HuangMing-HuangChenKENG-HSUEH LANYeh, Chun-NanChun-NanYeh2023-05-182023-05-182022-101664-3224https://scholars.lib.ntu.edu.tw/handle/123456789/631129Cholangiocarcinoma (CCA) is the second most common primary liver malignancy and carries a dismal prognosis due to difficulties in achieving an optimal resection, and poor response to current standard-of-care systemic therapies. We previously devised a CTLA4-PD-L1 DNA cancer vaccine (DNA vaccine) and demonstrated its therapeutic effects on reducing tumor growth in a thioacetamide (TAA)-induced rat intrahepatic CCA (iCCA) model. Here, we developed a CTLA4-PD-L1 chimeric protein vaccine (Protein vaccine), and examined its effects in the rat iCCA model. In a therapeutic setting, iCCA-bearing rats received either DNA plus Protein vaccines or Protein vaccine alone, resulting in increased PD-L1 and CTLA-4 antibody titers, and reduced iCCA tumor burden as verified by animal positron emission tomography (PET) scans. Treating iCCA-bearing rats with Protein vaccine alone led to the increase of CTAL4 antibody titers that correlated with the decrease of tumor SUV ratio, indicating regressed tumor burden, along with increased <i>CD8</i> and granzyme A (<i>GZMA</i>) expression, and decreased PD-L1 expression on tumor cells. In a preventive setting, DNA or Protein vaccines were injected in rats before the induction of iCCA by TAA. Protein vaccines induced a more sustained PD-L1 and CTLA-4 antibody titers compared with DNA vaccines, and was more potent in preventing iCCA tumorigenesis. Correspondingly, Protein vaccines, but not DNA vaccines, downregulated PD-L1 gene expression and hindered the carcinogenesis of iCCA. Taken together, the CTLA4-PD-L1 chimeric protein vaccine may function both as a therapeutic cancer vaccine and as a preventive cancer vaccine in the TAA-induced iCCA rat model.encholangiocarcinoma; immune checkpoint proteins; immune modulation; preventive vaccine; protein vaccine; therapeutic vaccine[SDGs]SDG3journal article10.3389/fimmu.2022.982196363413872-s2.0-85141200747WOS:000879454700001https://api.elsevier.com/content/abstract/scopus_id/85141200747