Understanding the Myeloid-specific IRF5-mediated Immune Response in Breast Cancer

Description

Many tumors are refractory to current immunotherapy due to counteracting immunosuppressive mechanisms within the tumor microenvironment. Understanding the cellular components and molecular pathways underlying the immunosuppression will informmore targeted approaches to cancer immunotherapy. Myeloid cells are the most abundant immune cells within the tumor, which often adopt a dysfunctional and tolerogenic phenotype that suppresses immune activation. Tumors with an increased proportion of inflammatory myeloid cells correlates with better disease outcome, demonstrating that properly activated myeloid cells can facilitate a protective anti-tumor response. Reprogramming tumor-infiltrated myeloid cells into an immunogenic state is therefore a promising strategy to overcome tumorinduced immunosuppression for effective immunotherapy. However, the factors that mediatemyeloid cell polarization and activation for anti-tumor immunity are not well-defined.Our preliminary results showed that myeloid-specific deletion of IRF5 exacerbates tumor growth in a murine breast cancer (BC) model. These results ascribe a positive role of IRF5 in regulating anti-tumor immunity. This proposal is motivated by elucidating how IRF5 in myeloid cells acts to inhibit tumor growth in the context of BC. IRF5 is a known transcription factor for regulating inflammation. However, the mechanisms by which IRF5 facilitates antitumor immunity is unknown; how myeloid-specific actions of IRF5 modulates BC tumor progression has not been revealed; the pathways and factors that regulate IRF5 activity in different myeloid subsets are not well-understood. This study will generate molecular insights in a cell type-specific manner for targeting IRF5 as an effective BC immunotherapy. Specifically, we will assess the immune landscape in BC tumors borne in mice lacking IRF5 only in myeloid cells to uncover the myeloid-specific role of IRF5 in coordinating antitumor immunity. We will test the efficacy of myeloid-specific IRF5 stimulation to inhibit BC growth. The phenotype and function of normal and IRF5-deficient myeloid cell subsets will be analyzed to delineate the cell type-specific actions of IRF5, and the factors regulating IRF5 activity in the different myeloid subtypes, including monocytes, macrophages, and neutrophils, will be dissected. Overall, results from this proposal will be directly applicable to designing novel immunotherapy for BC and other diseases where myeloid-mediated inflammation and immune processes underlie pathogenic mechanisms.