Mechanistic Targeting of the Type I Interferon Pathway to Improve Efficacy of Cancer Therapies

About This Grant

Project Summary Type I interferons (IFNs) are a family of cytokines that activate IFN stimulated gene expression via a well-defined JAK-STAT signal transduction pathway. They regulate cell proliferation, immune responses, and have been used in treatment of different types of cancers. Furthermore, IFN signaling is critical for the therapeutic efficacies of chemotherapy, radiation therapy, and immunotherapy. Despite its beneficial effects in cancer therapies, the current clinical use of IFN is limited. One major reason is the rapid attenuation of IFN signaling by a negative feedback loop in cancer cells, rendering them less responsive to the treatment. Therefore, targeting key negative regulators of this feedback loop likely offers a promising strategy to enhance IFN signaling and improve the efficacy of IFNs in cancer therapies. We cloned genes encoding mouse and human ubiquitin specific protease 18 (USP18) during a study of a leukemia fusion protein. USP18 expression is strongly upregulated by IFNs. Importantly for the current proposal, we identified USP18 as a major negative regulator of IFN signaling independent of its protease activity. Reduction of USP18 enhances and prolongs IFN activated JAK-STAT signaling and IFN stimulated gene expression. We hypothesize that mechanistic targeting of USP18 mediated negative regulation of IFN pathway will improve efficacy of IFNs in cancer therapies. Studies from our lab and others have shown that USP18 regulates cancer development. We discovered that depletion of USP18 impairs development of BCR-ABL-induced chronic myeloid leukemia (CML). CML belongs to a group of hematopoietic malignancies called myeloproliferative neoplasms (MPNs). MPNs are blood cancers caused by oncogenic mutations in bone marrow stem cells, leading to overproduction of myeloid cells and progression to acute myeloid leukemia (AML) with further mutations. MPNs are also known to contribute to suppression of the host immune system. Recent clinical evidence indicates that among different cancers, patients with MPNs exhibit the strongest responses to type I IFN therapies. We therefore consider that MPNs are an ideal model for us to investigate mechanistically how to improve IFN efficacy in cancer therapies by targeting USP18. We will test our hypothesis through the following specific aims. Specific Aim 1: Analyze the clinical and molecular impact of enhanced IFN signaling in cancer cells by targeting USP18. Specific Aim 2. Identification and mechanistic characterization of E3 ligases regulating USP18 degradation in MPN. Genetically engineered MPN mouse models and immunodeficient mice engrafted with human cells will be included in the study since they provide the only practical systems for evaluating the biological and therapeutic consequences of USP18 modulation in the context of the intact hematopoietic and immune microenvironment. The successful execution of this proposal will provide mechanistic anti-cancer effects of enhanced IFN signal pathway and connect this mechanistic knowledge to clinical applications. Furthermore, the characterization of USP18-degrading enzymes will pave the way for the development of molecular-glue-based USP18 degradation strategies. This approach will overcome the current limitations of IFN-based therapies in MPN, enhancing both their efficacy and patient outcomes.