5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma

• Main Authors: Nancy D. Ebelt, Edith Zuniga, Benjamin L. Johnson, Don J. Diamond, Edwin R. Manuel
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-03-01
• Series: Frontiers in Immunology
• Subjects: pancreatic ductal adenocarcinoma; transposable element; 5-azacytidine; anti-tumor immunity; tumor-associated antigens; immune evasion
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2020.00538/full

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.