T cell expressed microRNA-155 promotes antitumor immunity and immune checkpoint blockade responses in colon cancer through repression of Ship1

Abstract Colorectal cancer (CRC) is the 2 nddeadliest globally and has 3 rdhighest incidence mortality in United States. Advanced-stage disease incurable by current clinical standards. Thus, alternative treatments are being explored, including immune checkpoint blockade (ICB) to prevent T cell inactivation tumors. ICB induces a robust response patients with microsatellite instability-high (MSI-H) metastatic CRC. However, most CRC not responsive ICB. Our analysis revealed MSI-H exhibit an cell-mediated inflammatory tumor microenvironment (TME) that associated expression of microRNAs (miRs) linked regulation. By studying cell-associated miRs colon patients, through Crispr-Cas9 based vivo screening, we identified miR-155 as miR highly patients. was necessary for responses multiple preclinical models promoted Th1-helper cytotoxic lymphocyte enrichment TME, reflecting response. controls immunity repressing network target genes, notably SHIP1. Loss derepressed SHIP-1 gene our study. Additionally, expressed human tumor-associated cells, lower correlating better patient outcomes. In vivo, demonstrated inhibition partially restored mice specifically lacking miR-155. These findings suggest dependence on its targets effective efficacy cancer, identifying candidate biomarker therapeutic. Supported grants from NIH (F30 CA260977)