Tumor-intrinsic IRF5 reprograms the tumor immune microenvironment to inhibit breast cancer metastasis

Abstract

Abstract Metastasis of breast cancer and recurrence to incurable disease are leading causes of mortality. Metastasis is driven by extensive cooperation between a tumor and its microenvironment, resulting in the adaptation of molecular mechanisms that evade the immune system and enable pre-metastatic niche (PMN) formation. Little is known of the tumor-intrinsic factors that regulate these mechanisms. Here we show that expression of the transcription factor interferon regulatory factor 5 (IRF5) in breast cancer clinically correlates with tumor immunogenicity, increased T cell and M1 macrophage recruitment and prolonged survival. Conversely, loss of tumor-intrinsic Irf5 establishes a tumor microenvironment and PMN that supports metastasis. Mechanistically, Irf5 alters the composition and secretion of tumor-derived extracellular vesicles (t-dEVs). Upon whole-body pre-conditioning with t-dEVs from Irf5-positive or −negative breast cancer cells, we found increased lung metastatic colonization that replicated findings from orthotopically implanted breast cancer cells. Collectively, our findings uncover an essential role for IRF5 in breast cancer metastasis through its regulation of t-dEV and immune reprogramming.