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Updated: Aug 16, 2026
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Identification of novel human CTL epitopes and their agonist epitopes of mesothelin
Junko Yokokawa1, Claudia Palena, Philip Arlen
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Purpose:
Mesothelin is overexpressed in many pancreatic and ovarian cancers, mesotheliomas, and other tumor types. Clinical trials are ongoing using immunotoxins to target mesothelin, and patients immunized with allogeneic pancreatic tumor cell lines have shown immune responses to previously defined mesothelin epitopes. The purpose of this study was to define novel mesothelin CTL epitopes and, more importantly, agonist epitopes that would more efficiently activate human T cells to more efficiently lyse human tumors.
Experimental Design And Results:
Two novel mesothelin HLA-A2 epitopes were defined. T-cell lines generated from one of these epitopes were shown to lyse pancreatic and ovarian tumor cells. Several agonist epitopes were defined and were shown to (a) have higher affinity and avidity for HLA-A2, (b) activate mesothelin-specific T cells from normal individuals or cancer patients to a greater degree than the native epitope in terms of induction of higher levels of IFN-gamma and the chemokine lymphotactin, and (c) lyse several mesothelin-expressing tumor types in a MHC-restricted manner more effectively than T cells generated using the native peptide. External beam radiation of tumor cells at nontoxic levels was shown to enhance the expression of mesothelin and other accessory molecules, resulting in a modest but statistically significant increase in tumor cell lysis by mesothelin-specific T cells.
Conclusions:
The identification of novel CTL agonist epitopes supports and extends observations that mesothelin is a potential target for immunotherapy of pancreatic and ovarian cancers, as well as mesotheliomas.
Insights
Researchers identified new mesothelin epitopes that activate T cells more effectively. These findings support mesothelin as a promising target for immunotherapy against pancreatic cancer, ovarian cancer, and mesothelioma.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Mesothelin is a protein overexpressed in pancreatic cancer, ovarian cancer, and mesothelioma.
- Ongoing clinical trials utilize immunotoxins targeting mesothelin.
- Previous studies showed immune responses to known mesothelin epitopes.
Purpose of the Study:
- To identify novel mesothelin cytotoxic T lymphocyte (CTL) epitopes.
- To define agonist epitopes for enhanced human T cell activation.
- To improve T cell-mediated lysis of human tumors.
Main Methods:
- Definition of novel mesothelin HLA-A2 epitopes.
- Generation and characterization of T-cell lines.
- Assessment of T cell activation and tumor cell lysis.
- Evaluation of non-toxic radiation effects on tumor cells.
Main Results:
- Two novel mesothelin HLA-A2 epitopes were identified.
- Defined agonist epitopes demonstrated higher affinity and avidity for HLA-A2.
- Agonist epitopes enhanced T cell activation, increasing IFN-gamma and lymphotactin levels.
- Mesothelin-specific T cells showed more effective lysis of mesothelin-expressing tumors.
- Low-dose radiation enhanced mesothelin expression and T cell-mediated tumor lysis.
Conclusions:
- Novel CTL agonist epitopes were identified, supporting mesothelin as a viable immunotherapy target.
- These findings advance the potential for treating pancreatic and ovarian cancers, and mesotheliomas.
