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

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Advanced colorectal cancer (CRC) presents a significant clinical challenge with poor survival rates.
• Current immune checkpoint inhibitors (ICIs) show promise but lack optimal predictors of patient response.
• Novel therapeutic targets are needed to improve outcomes in advanced cancers.

Purpose of the Study:

• To identify key microRNAs regulating CD8+ T-cell function in anti-tumor immunity.
• To determine the role of microRNA-155 (miR-155) in T-cell responses to anti-PD-1 therapy.
• To develop a predictive gene signature for ICI efficacy.

Main Methods:

• An in vivo CRISPR-Cas9 screen was employed to identify functional microRNAs expressed by tumor antigen-specific CD8+ T cells.
• The necessity of miR-155 for anti-PD-1 responses was assessed.
• Mechanisms of miR-155 action, including target gene repression and T-cell differentiation, were investigated.
• A gene signature associated with miR-155-dependent CD8+ T-cell transcription was identified.

Main Results:

• MicroRNA-155 (miR-155) was identified as essential for CD8+ T-cell infiltration in tumors.
• T-cell miR-155 is critical for anti-PD-1 therapy efficacy by regulating T-cell differentiation.
• miR-155 represses Ship-1, influences Tcf-1 and stemness, and enhances Cxcr6 expression and effector functions.
• A miR-155-dependent gene signature accurately predicts ICI responses across 12 cancer types.

Conclusions:

• miR-155 acts as a central regulator of CD8+ T-cell-mediated cancer immunity.
• miR-155 is a key determinant of response to immune checkpoint inhibitors.
• Targeting miR-155 or leveraging its associated gene signature offers potential therapeutic strategies for enhancing cancer immunotherapy.