Repression of the type i interferon pathway underlies MYC-and KRAS-dependent evasion of NK and B cells in pancreatic ductal adenocarcinoma

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Abstract

MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC– MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival. SIGNIFICANCE: We define herein a novel mechanism of evasion of NK cell–mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC.

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Muthalagu, N., Monteverde, T., Raffo-Iraolagoitia, X., Wiesheu, R., Whyte, D., Hedley, A., … Murphy, D. J. (2020). Repression of the type i interferon pathway underlies MYC-and KRAS-dependent evasion of NK and B cells in pancreatic ductal adenocarcinoma. Cancer Discovery, 10(6), 872–887. https://doi.org/10.1158/2159-8290.CD-19-0620

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