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Updated: Aug 6, 2026
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Fibroblast-specific ablation of MHC-I antigen presentation via the IGF2 axis cripples CD8+ T cell surveillance in
Daqiang Song1, Xiaofang Li1, Qian Xiao2,3
1Department of Breast and Thyroid Surgery, Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract:
How cancer-associated fibroblasts (CAFs) dictate CD8+ T cell dysfunction during lung cancer remains unclear. Through single-cell analysis of 84 human NSCLC samples, we identified insulin-like growth factor 2 (IGF2) as a key immunosuppressive factor in a specific CAF subset. IGF2+ CAF infiltration correlated with CD8+ T cell dysfunction. Fibroblast-specific IGF2 knockout enhanced antigen presentation cell-autonomously via major histocompatibility complex class I (MHC-I), boosting CD8+ T cell effector function, tumor suppression, survival, and PD-1 blockade synergy. Mechanistically, IGF2 sustained MYC signaling to up-regulate DNA methyltransferase 1 (DNMT1), which methylated the STAT1 promoter, epigenetically silencing STAT1. This impaired MHC-I presentation and CD8+ T cell activation. Clinically, high IGF2 levels associated with reduced CD8+ T cell cytotoxicity and poor outcomes. An IGF2+ fibroblast signature predicted worse response to immunotherapy in multiple cohorts. Our findings establish IGF2 as a central regulator of CAF-mediated immunosuppression and a stromal target for enhancing immunotherapy in lung cancer.
Insights
Cancer-associated fibroblasts (CAFs) suppress CD8+ T cells in lung cancer via IGF2. Blocking IGF2 restores T cell function and improves immunotherapy response, offering a new therapeutic target.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cancer-associated fibroblasts (CAFs) play a critical role in the tumor microenvironment, influencing immune cell function.
- The precise mechanisms by which CAFs induce CD8+ T cell dysfunction in non-small cell lung cancer (NSCLC) are not fully understood.
Purpose of the Study:
- To investigate the role of CAFs in CD8+ T cell dysfunction in NSCLC.
- To identify specific molecular factors secreted by CAFs that mediate immunosuppression.
- To explore the therapeutic potential of targeting these factors for enhancing anti-tumor immunity.
Main Methods:
- Single-cell RNA sequencing and analysis of 84 human NSCLC samples.
- Functional studies involving fibroblast-specific IGF2 knockout models.
- Analysis of antigen presentation, T cell activation, and tumor growth.
- Investigation of molecular pathways including MYC, DNMT1, and STAT1 methylation.
- Clinical correlation analysis with patient outcomes and immunotherapy response.
Main Results:
- A specific subset of CAFs expressing insulin-like growth factor 2 (IGF2) was identified as a key immunosuppressive factor.
- IGF2+ CAF infiltration correlated significantly with CD8+ T cell dysfunction and poor patient prognosis.
- IGF2 knockout in fibroblasts enhanced MHC-I presentation, boosted CD8+ T cell effector function, and improved tumor suppression.
- Mechanistically, IGF2 promoted MYC signaling, leading to DNMT1 upregulation, STAT1 promoter methylation, and epigenetic silencing of STAT1, impairing T cell activation.
- An IGF2+ fibroblast signature predicted poor response to immunotherapy across multiple patient cohorts.
Conclusions:
- IGF2 is a critical mediator of CAF-driven immunosuppression in lung cancer.
- Targeting IGF2 in stromal cells can restore CD8+ T cell function and enhance anti-tumor immunity.
- IGF2 represents a promising therapeutic target for improving the efficacy of immunotherapy in NSCLC.
