Related Experiment Video
Updated: Sep 14, 2025
Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Targeted degradation of sICOSL reverses cytotoxic T cells dysfunction
Zhenghao Wu1,2,3, Peng Zheng4,5, Ruobing Qi6
1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wu_zhenghao@126.com.
Abstract:
Dysfunction of cytotoxic T cells (CTL) remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that increased soluble form of ICOSL (sICOSL) induced CTL dysfunction and was associated with shorter survival of patients with breast cancer. sICOSL emerged as a formidable adversary to CTLs, by directly triggering ICOS internalization and subsequent degradation-a critical blow to the co-stimulatory machinery essential for CTL activation. Our research shows that dipeptidyl peptidase-4 (DPP4) mainly breaks down sICOSL. Notably, certain chemotherapeutic drugs activate the histone methyltransferase Enhancer of zeste homolog 2 (EZH2), which in turn suppresses DPP4 expression. To address this issue, we have developed nanobody-DPP4 fusion proteins that can specifically degrade sICOSL, achieving substrate selectivity and tumor targeting. Overall, This work unveils that sICOSL orchestrates CTL dysfunction, and establishs targeted degradation of sICOSL as a new strategy for immunotherapy.
Insights
Increased soluble ICOSL (sICOSL) impairs cytotoxic T cell (CTL) function, worsening breast cancer survival. Researchers developed nanobody-DPP4 fusion proteins to degrade sICOSL, offering a novel cancer immunotherapy strategy.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Cytotoxic T cell (CTL) dysfunction is a key mechanism of tumor immune evasion, leading to poor cancer patient survival.
- Elevated soluble ICOSL (sICOSL) levels correlate with reduced survival in breast cancer patients, indicating its role in disease progression.
Purpose of the Study:
- To investigate the mechanism by which sICOSL induces CTL dysfunction.
- To identify therapeutic strategies for targeting sICOSL in cancer immunotherapy.
Main Methods:
- Investigated the interaction between sICOSL and CTLs, focusing on ICOS receptor internalization and degradation.
- Identified dipeptidyl peptidase-4 (DPP4) as the primary enzyme responsible for sICOSL breakdown.
- Developed nanobody-DPP4 fusion proteins for targeted sICOSL degradation.
Main Results:
- sICOSL directly causes CTL dysfunction by promoting ICOS receptor degradation, crucial for T cell activation.
- DPP4 enzyme activity is suppressed by chemotherapeutic drugs via EZH2-mediated epigenetic changes.
- Novel nanobody-DPP4 fusion proteins demonstrated selective degradation of sICOSL and tumor targeting capabilities.
Conclusions:
- sICOSL is a critical mediator of CTL dysfunction and a negative prognostic factor in breast cancer.
- Targeted degradation of sICOSL represents a promising new avenue for cancer immunotherapy.
- The developed nanobody-DPP4 fusion proteins offer a potential therapeutic tool for enhancing anti-tumor immunity.
More Related Videos
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
08:59Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
Published on: December 11, 2017
Related Concept Videos
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:27Tumor Immunotherapy