A microRNA-regulated transcriptional state defines intratumoral CD8+ T cells that respond to immunotherapy
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<sup>+</sup> T cell-infiltrated tumors through an unbiased in vivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8<sup>+</sup> T cell-expressed microRNAs. T cell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.
Authors
- Arevik Ghazaryan (ORCID: https://orcid.org/0000-0002-4718-4164)
- Morgan C. Nelson (ORCID: https://orcid.org/0000-0001-9812-499X)
- Aik Choon Tan (ORCID: https://orcid.org/0000-0003-2955-8369)
- Emmanuel Stephen‐Victor (ORCID: https://orcid.org/0000-0001-5049-7017)
- Ryan M. O’Connell (ORCID: https://orcid.org/0000-0003-0860-1401)
- Cindy Barba
- Colton J. Hernandez (ORCID: https://orcid.org/0000-0002-5705-0856)
- Van B. Tran
- Kaylyn M. Bauer (ORCID: https://orcid.org/0000-0002-5498-9083)
- Soh-Hyun Lee (ORCID: https://orcid.org/0000-0001-6620-8961)
- Dinesh S. Rao (ORCID: https://orcid.org/0000-0002-0794-9337)
- Matthew A. Williams (ORCID: https://orcid.org/0000-0002-4721-4482)
- June L. Round (ORCID: https://orcid.org/0000-0002-7158-9874)
- Muhammad Zaki Hidayatullah Fadlullah (ORCID: https://orcid.org/0000-0002-3111-8090)
- Warren P. Voth (ORCID: https://orcid.org/0000-0003-0632-6979)
- William W. Tang (ORCID: https://orcid.org/0000-0001-7036-6460)
- Micah J. Drummond (ORCID: https://orcid.org/0000-0001-5961-8890)
- Allison M. Weis (ORCID: https://orcid.org/0000-0001-9991-1661)
- H. Atakan Ekiz (ORCID: https://orcid.org/0000-0001-7718-6841)
- Jacob Tantalla (ORCID: https://orcid.org/0000-0002-9565-4888)
- Ellen J. Beswick (ORCID: https://orcid.org/0000-0003-4147-5777)
- Z Busra Agir
- Amber Thibeaux
- Ben Battistone
Institutions
- Izmir Institute of Technology (TR)
- University of Kentucky (US)
- University of California, Los Angeles (US)
- University of Utah (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115301
- Citations
- 8
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 8.36
Funders
- National Institutes of Health