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.
Highlights
Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) [1] and antiprogrammed death 1 (PD-1) [2], discovered by James P
immune-checkpoint inhibitors (ICIs) showed modest efficacy in the treatment of Intrahepatic cholangiocarcinoma (iCCA) [20]; currently, pembrolizumab is merely indicated for iCCA patients with microsatellite instability-high (MSI-H) or deficient mismatch repair [21]
The mouse CTLA4 (mCTLA4)-PD-L1 DNA vaccine was generated by inserting the human IL2 protein sequence (MRRMQLLLLIALSLALVTNS) for enhancing protein secretion [28], mouse ctla4 nt 316-14449, and mouse cd274 nt 163-1143 into the pVAC1 vector (Figure S1); mGM-CSF-mEGF is a fusion protein
Summary
Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) [1] and antiprogrammed death 1 (PD-1) [2], discovered by James P. Monoclonal antibodies targeting immune checkpoints were designed to block the negative interactions between cancer and immune cells, thereby enhancing tumor immunity. Immune-checkpoint inhibitors (ICIs) are widely used in the treatment of various cancers such as melanoma [3,4], nonsmall-cell lung cancer [5,6,7], small-cell lung cancer [8,9,10,11], and urothelial carcinoma [12]. Most patients with iCCA are diagnosed at an advanced stage and have extremely poor prognosis. ICIs showed modest efficacy in the treatment of iCCA [20]; currently, pembrolizumab is merely indicated for iCCA patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) [21]
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