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Updated: May 30, 2026
Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Cytotoxic activity of immunotoxin SS1P is modulated by TACE-dependent mesothelin shedding
Yujian Zhang1, Oleg Chertov, Jingli Zhang
1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Abstract:
Mesothelin is a cell-surface tumor-associated antigen expressed in several human cancers. The limited expression of mesothelin on normal tissues and its high expression in many cancers make it an attractive candidate for targeted therapies using monoclonal antibodies, immunoconjugates, and immunotoxins. Mesothelin is actively shed from the cell surface and is present in the serum of patients with malignant mesothelioma, which could negatively affect the response to these therapies. We have found that mesothelin sheddase activity is mediated by a TNF-α converting enzyme (TACE), a member of the matrix metalloproteinase/a disintegrin and metalloprotease family. We showed that EGF and TIMP-3 act through TACE as endogenous regulators of mesothelin shedding. We also found that reducing shedding significantly improved the in vitro cytotoxicity of immunotoxin SS1P, which targets mesothelin and is currently in clinical trials for the treatment of patients with mesothelioma and lung cancer. Our findings provide a mechanistic understanding of mesothelin shedding and could help improve mesothelin-based targeted therapies.
Insights
Tumor antigen mesothelin shedding is mediated by TNF-α converting enzyme (TACE). Inhibiting mesothelin shedding enhances the effectiveness of targeted immunotherapies like SS1P for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mesothelin is a tumor-associated antigen highly expressed in cancers, making it a target for therapies.
- Mesothelin shedding into serum can hinder the efficacy of targeted treatments like immunotoxins.
- Understanding mesothelin shedding mechanisms is crucial for improving cancer therapies.
Purpose of the Study:
- To identify the enzyme responsible for mesothelin shedding.
- To investigate the regulation of mesothelin shedding.
- To determine if reducing mesothelin shedding improves the efficacy of mesothelin-targeted immunotoxins.
Main Methods:
- Enzyme assays to identify mesothelin sheddase activity.
- Investigated the role of TNF-α converting enzyme (TACE) in mesothelin shedding.
- Assessed the impact of inhibiting shedding on immunotoxin SS1P cytotoxicity in vitro.
Main Results:
- Identified TNF-α converting enzyme (TACE) as the primary mediator of mesothelin shedding.
- Demonstrated that EGF and TIMP-3 regulate mesothelin shedding via TACE.
- Showed that reducing mesothelin shedding significantly enhanced the in vitro efficacy of the immunotoxin SS1P.
Conclusions:
- Mesothelin shedding is regulated by TACE, with EGF and TIMP-3 as key modulators.
- Inhibiting TACE-mediated mesothelin shedding improves the efficacy of mesothelin-targeted immunotherapies.
- These findings offer a mechanistic basis for enhancing mesothelin-based cancer treatments.
