Targeting TCF19 sensitizes MSI endometrial cancer to anti-PD-1 therapy by alleviating CD8+ T cell exhaustion via TRIM14-IFN-β axis
Related Experiment Video
Updated: Jul 19, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Xinyue Ma1, Qiuman Wang1, Chenggong Sun1
1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.
Abstract:
Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon β (IFN-β) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-β facilitates CD8+ T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8+ T cell exhaustion and synergizing with ICB in tumor treatment.
Insights
Transcription factor 19 (TCF19) drives immune exhaustion in endometrial cancer (EC). Inhibiting TCF19 combined with immune checkpoint blockade (ICB) therapy shows enhanced anti-tumor responses, offering a new treatment strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) therapies are effective for microsatellite instable (MSI) endometrial cancer (EC) by restoring anti-tumor immunity.
- Understanding mechanisms of T cell exhaustion is crucial for improving EC treatment outcomes.
Purpose of the Study:
- To investigate the role of transcription factor 19 (TCF19) in MSI endometrial cancer (EC) and its impact on T cell exhaustion.
- To explore the potential of targeting TCF19 in combination with ICB therapy for enhanced anti-tumor effects.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA)-EC cohort to identify differentially expressed genes.
- Investigated the TCF19-TRIM14 axis and its downstream signaling pathways (TBK1-IRF3-IFN-β).
- Utilized humanized models to assess the efficacy of TCF19 inhibition combined with ICB therapy.
Main Results:
- TCF19 is significantly elevated in MSI EC and associated with poor prognosis and immune exhaustion.
- TCF19 promotes tripartite motif-containing 14 (TRIM14) transcription, leading to hyperactive TBK1-IRF3-IFN-β signaling.
- Elevated interferon-β (IFN-β) secretion driven by TCF19 facilitates CD8+ T cell exhaustion.
- Combined TCF19 inhibition and ICB therapy demonstrated superior anti-tumor responses in humanized models.
Conclusions:
- TCF19 plays a critical role in promoting tumorigenicity and immune exhaustion in MSI EC.
- Targeting TCF19 is a promising strategy to alleviate CD8+ T cell exhaustion.
- Combining TCF19 inhibition with ICB therapy offers a synergistic approach for effective endometrial cancer treatment.
More Related Videos
07:46Author Spotlight: Advancing Reproductive Immunology with a Protocol for the Quantitative Evaluation of Endometrial Immune Cells
Published on: October 13, 2023
07:05TGF-β-mediated Endothelial to Mesenchymal Transition EndMT and the Functional Assessment of EndMT Effectors using CRISPR/Cas9 Gene Editing
Published on: February 26, 2021
