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https://hdl.handle.net/11147/15413
Title: | A MicroRNA-Regulated Transcriptional State Defines Intratumoral CD8+ Tcells That Respond To Immunotherapy | Authors: | Tang, W.W. Battistone, B. Bauer, K.M. Weis, A.M. Barba, C. Fadlullah, M.Z.H. O'Connell, R.M. Ekiz, Hüseyin Atakan |
Keywords: | Anti-Pd-1 Biomarker Cd8<Sup>+</Sup> T Cell Colorectal Cancer Cp: Cancer Cp: Immunology Cxcr6 Immune Checkpoint Inhibition Immunotherapy Microrna-155 Ship-1 Tcf-1 |
Publisher: | Elsevier B.V. | 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. © 2025 The Author(s) | URI: | https://doi.org/10.1016/j.celrep.2025.115301 https://hdl.handle.net/11147/15413 |
ISSN: | 2639-1856 |
Appears in Collections: | Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection |
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