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A microRNA-regulated transcriptional state defines intratumoral CD8+T cells that respond to immunotherapy

ABSTRACT: Rising rates of advanced-stage colorectal cancer (CRC) and poor survival rates necessitate effective therapeutic options. Immune checkpoint inhibition (ICI), specifically anti-PD-1 therapy, shows potential, but clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8 T cell infiltrated tumors through an unbiased in vivo Crispr-Cas9 screen of tumor-antigen-specific CD8 T cell-related miRNAs. MiR-155 was necessary for a vital CD8 T cell differentiation cascade by repressing Ship-1, thereby inhibiting stemness and Tcf-1 while enhancing effector function and Cxcr6 expression, an indispensable aspect of anti-tumor and -PD-1 responses. Through a miR-155-dependent CD8 T cell transcriptional profile, we identified a gene signature that predicts anti-PD-1 responses across ten cancers. Taken together, our findings support a model whereby miR-155 serves as a central axis for CD8 T cell-dependent immunity in CRC and anti-PD-1 responses against multiple cancers that may be leveraged therapeutically or as a biomarker.

ORGANISM(S): Mus musculus

PROVIDER: GSE262873 | GEO | 2025/02/10

REPOSITORIES: GEO

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