Abstract
Tumors evolve a variety of mechanisms to escape immune detection while expressing tumor-promoting molecules that can be immunogenic. Here, we show that transposable elements (TE) and gene encoded, tumor-associated antigens (TAA), which can be both highly immunogenic and tumor-promoting, are significantly upregulated during the transition from pre-malignancy to malignancy in an inducible model of pancreatic ductal adenocarcinoma (PDAC). Coincident with the increased presence of TEs and TAAs was the downregulation of gene transcripts associated with antigen presentation, T cell recruitment and intrinsic anti-viral responses, suggesting a unique strategy employed by PDAC to possibly augment tumorigenesis while escaping detection by the immune system. In vitro treatment of mouse and human PDAC cell lines with the DNA methyltransferase inhibitor 5-azacytidine (Aza) resulted in augmented expression of transcripts for antigen presentation machinery and T cell chemokines. When immunocompetent mice implanted with PDAC were therapeutically treated with Aza, we observed significant tumor regression that was not observed in immunocompromised mice, implicating anti-tumor immunity as the principal mechanism of tumor growth control. Analysis of PDAC tumors, immediately following Aza treatment in immunocompetent mice, revealed a significantly greater infiltration of T cells and various innate immune subsets compared to control treatment, suggesting that Aza treatment enhances tumor immunogenicity. Thus, augmenting antigen presentation and T cell chemokine expression using DNA methyltransferase inhibitors could be leveraged to potentiate adaptive anti-tumor immune responses against PDAC.
Highlights
Tumorigenesis involves extensive epigenetic reprogramming as cells transform and evolve
We confirm that treatment of pancreatic ductal adenocarcinoma (PDAC) cells, with the DNA methyltransferase inhibitors (DNMTi) 5-Azacytidine (Aza), results in the induction of gene transcripts involved in antigen presentation and T cell recruitment, which likely contributes to tumor growth control observed in vivo
Intraperitoneal administration of tamoxifen in 4–5 week old mice consistently results in a steady chronologic progression to PDAC that is equivalent to that observed in humans: acinarductal metaplasia (ADM) > pancreatic intraepithelial neoplasia (PanIN) > PDAC > liver and lung metastases [40]
Summary
Tumorigenesis involves extensive epigenetic reprogramming as cells transform and evolve. IFN-γ response genes and genes that encode major histocompatibility (MHC) class molecules and other antigen presentation machinery can be hypermethylated or mutated leading to reduced tumor immunogenicity [18,19,20]. We confirm that treatment of PDAC cells, with the DNMTi 5-Azacytidine (Aza), results in the induction of gene transcripts involved in antigen presentation and T cell recruitment, which likely contributes to tumor growth control observed in vivo. Therapeutic Aza treatment correlated with an overall increase in tumor immune infiltrate with specific increases in CD4 and CD8 T cells, indicating an important role for adaptive anti-tumor immunity in tumor control These data support the potential use of DNMTi as a therapeutic strategy to enhance anti-tumor immunity in PDAC and various other malignancies
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