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Comprehensive Evaluation of Immune-Checkpoint DNA Cancer Vaccines in a Rat Cholangiocarcinoma Model.

ABSTRACT: Cholangiocarcinoma (CCA) is a malignant tumor with aggressive biological behavior. Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and antiprogrammed death 1 (PD-1) are critical immune-checkpoint molecules that repress T-cell activation. The DNA vaccine potential against CTLA4 and PD-1 in CCA is unknown. We used a thioacetamide (TAA)-induced intrahepatic cholangiocarcinoma (iCCA) rat model to investigate the DNA vaccine potential against CTLA4, PD-1, and PD-L1. We detected PD-L1 expression in CCA and CD8⁺ T-cell infiltration during CCA progression in rats. We validated antibody production, carcinogenesis, and CD8⁺ T-cell infiltration in rats receiving DNA vaccination against PD-1, PD-L1, or CTLA4. In our TAA-induced iCCA rat model, the expression of PD-L1 and the infiltration of CD8⁺ T cells increased as in rat CCA tumorigenesis. PD-1 antibodies in rats were not increased after receiving PD-1 DNA vaccination, and CCA tumor growth was not suppressed. However, in rats receiving PD-L1-CTLA4 DNA vaccination, CCA tumor growth was inhibited, and the antibodies of PD-L1 and CTLA4 were produced. Furthermore, the number of CD8⁺ T cells was enhanced after PD-L1-CTLA4 DNA vaccination. DNA vaccination targeting CTLA4-PD-L1 triggered the production of specific antibodies and suppressed tumor growth in TAA-induced iCCA rats.

SUBMITTER: Pan YR

PROVIDER: S-EPMC7712087 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Comprehensive Evaluation of Immune-Checkpoint DNA Cancer Vaccines in a Rat Cholangiocarcinoma Model.

Pan Yi-Ru YR Wu Chiao-En CE Chen Ming-Huang MH Huang Wen-Kuan WK Shih Hsuan-Jen HJ Lan Keng-Li KL Yeh Chun-Nan CN

Vaccines 20201124 4

Cholangiocarcinoma (CCA) is a malignant tumor with aggressive biological behavior. Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and antiprogrammed death 1 (PD-1) are critical immune-checkpoint molecules that repress T-cell activation. The DNA <i>vaccine potential</i> against CTLA4 and PD-1 in CCA is unknown. We used a thioacetamide (TAA)-induced intrahepatic <i>cholangiocarcinoma</i> (iCCA) rat model to investigate the DNA vaccine potential against CTLA4, PD-1, and PD-L1. ...[more]

PMID: 33255375

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Project description:BackgroundCholangiocarcinoma (CCA) encompasses a heterogeneous group of malignant tumors with dismal prognosis and increasing incidence worldwide. Both late diagnosis due to the lack of early symptoms and the refractory nature of these tumors seriously compromise patients' welfare and outcomes.SummaryDuring the last decade, immunotherapy and, more specifically, modulation of immune checkpoints-mediated signaling pathways have been under the spotlight in the field of oncology, emerging as a potential therapeutic approach for the treatment of several cancers, including CCA. Generally, high expression levels of immune checkpoints in patients with CCA have been associated with worse clinical outcomes, particularly with shorter overall survival and relapse-free survival. Thus, immune checkpoint inhibitors (ICIs), which mainly constitute different monoclonal antibodies, have been developed in order to hamper the immune checkpoint-mediated pathways. Interestingly, chemotherapy may increase the expression of immune checkpoints, while other therapeutic approaches such as ablative and targeted therapies may enhance their antitumor activity. In this sense, several clinical trials evaluated the safety and efficacy of ICIs for CCA, both as a monotherapy and in combination with other ICIs or loco-regional and systemic therapies. Additionally, many other clinical trials are currently ongoing and results are eagerly awaited. Here, we summarize the key aspects of immune checkpoint molecules as prognostic factors and therapeutic targets in CCA, highlighting the most recent advances in the field and future research directions.Key messages(1) Effective therapeutic approaches for CCA are urgently needed. (2) Expression levels of immune checkpoints in patients with CCA have been proposed to be related with clinical outcomes. (3) Combination of different ICIs may outperform the efficacy of ICI monotherapy for CCA treatment. (4) Recent studies point toward the combination of ICIs and other common therapies, especially chemotherapy, as a promising strategy for treatment of CCA patients.

Dataset Information

Comprehensive Evaluation of Immune-Checkpoint DNA Cancer Vaccines in a Rat Cholangiocarcinoma Model.

Publications

Comprehensive Evaluation of Immune-Checkpoint DNA Cancer Vaccines in a Rat Cholangiocarcinoma Model.

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