Interferon E as a Tumor Suppressor and Potential Therapeutic in Pancreatic Cancer

PROJECT SUMMARY/ ABSTRACT Loss of chromosome 9p21.3 is the most common homozygous deletion across cancers, including pancreatic ductal adenocarcinoma (PDAC), and it is strongly linked to poor prognosis and increased resistance to immune checkpoint blockade (ICB). 9p21.3 deletions invariably affect the tumor suppressor genes CDKN2A/B, yet often include a linked cluster of type I interferon (IFN) genes, which encode cytokines with antiviral, antiproliferative, and immune modulatory effects. While often overlooked, our laboratory recently found that co-deletion of the entire type I IFN cluster contributes to an immunosuppressive microenvironment, leading to reduced immune surveillance, increased metastasis, and resistance to ICB in mouse models of PDAC. Preliminary data suggest that co-deletion of Ifne, the type I IFN gene closest to Cdkn2a/b, is sufficient to disrupt tumor immune surveillance and promote metastasis. The overall objective of this proposal is to understand the role, regulation, and therapeutic potential of Ifne in PDAC immune surveillance. Aim 1: Determine the specific contributions of IFNE to tumor immune surveillance. I will decisively assess if Ifne is a tumor suppressor in the context of Cdkn2a loss by evaluating the effects of Ifne deletion in orthotopic PDAC mouse models by measuring tumor growth, metastasis, and immune infiltrates. I will also test recombinant IFNE (rIFNE) as a potential therapy. Aim 2: Characterize the regulation of Ifne during PDAC tumor progression. I will profile Ifne expression in PDAC and the tumor microenvironment and will test the hypothesis that Ifne is induced early during tumor development by mutant Kras signaling. Training plan: I will work with an interdisciplinary team of mentors and collaborators to gain expertise in cancer biology, molecular and cell biology, and immunology. The skills that I will develop over the course of this project will prepare me for a career as an independent researcher.