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

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