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Abstract
The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet 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 identifying functional tumor antigen-specific CD8+ T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8 + T cell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based on an underlying miR-155-dependent CD8 + T cell transcriptional profile, we identify a gene signature that predicts ICI responses across 12 diverse cancers. Together, our findings support a model whereby miR- 155 serves as a central regulator of CD8 + T cell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.
Document Type
Article
Publication Date
2-2025
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.celrep.2025.115301
Funding Information
We would like to thank the following University of Utah Core Facilities: the HCI-High-Throughput Genomics and Bioinformatics Resources for performing scRNA-seq, the HSC Flow Cytometry Core Facility for cell sorting, and the DNA/Peptide Synthesis Core for primer synthesis. W.W.T. was funded by NIH grant 5F30CA260977, and R.M.O. was funded by NIH grant 5R01AG079477.
Repository Citation
Tang, William W.; Battistone, Ben; Bauer, Kaylyn M.; Weis, Allison M.; Barba, Cindy; Fadlullah, Muhammad Zaki Hidayatullah; Ghazaryan, Arevik; Tran, Van B.; Lee, Soh-Hyun; Agir, Z. Busra; Nelson, Morgan C.; Victor, Emmanuel Stephen; Thibeaux, Amber; Hernandez, Colton; Tantalla, Jacob; Tan, Aik C.; Rao, Dinesh; Williams, Matthew; Drummond, Micah J.; Beswick, Ellen J.; Round, June L.; Ekiz, H. Atakan; Voth, Warren P/; and O’Connell, Ryan M., "A microRNA-regulated transcriptional state defines intratumoral CD8+ T cells that respond to immunotherapy" (2025). Markey Cancer Center Faculty Publications. 292.
https://uknowledge.uky.edu/markey_facpub/292
Notes/Citation Information
© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).