1. Mesothelin- and nucleolin-specific T cells from combined short peptides effectively kill triple-negative breast cancer cells.
- Author
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Thongchot S, Aksonnam K, Prasopsiri J, Warnnissorn M, Sa-Nguanraksa D, O-Charoenrat P, Thuwajit P, Yenchitsomanus PT, and Thuwajit C
- Subjects
- Humans, Female, Peptides, Cell Line, Tumor, T-Lymphocytes immunology, Middle Aged, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Immunotherapy, Adoptive methods, Adult, Cytokines metabolism, Triple Negative Breast Neoplasms immunology, Mesothelin, RNA-Binding Proteins immunology, Nucleolin, GPI-Linked Proteins, Phosphoproteins
- Abstract
Background: Triple-negative breast cancer (TNBC), known for its aggressiveness and limited treatment options, presents a significant challenge. Adoptive cell transfer, involving the ex vivo generation of antigen-specific T cells from peripheral blood mononuclear cells (PBMCs), emerges as a promising approach. The overexpression of mesothelin (MSLN) and nucleolin (NCL) in TNBC samples underscores their potential as targets for T cell therapy. This study explored the efficacy of multi-peptide pulsing of PBMCs to generate MSLN/NCL-specific T cells targeting MSLN
+ /NCL+ TNBC cells., Methods: TNBC patient samples were confirmed for both MSLN and NCL expression via immunohistochemistry. Synthesized MSLN and NCL peptides were combined and administered to activate PBMCs from healthy donors. The cancer-killing ability of the resultant T cells was assessed using crystal violet staining, and their subtypes and cytotoxic cytokines were characterized through flow cytometry and cytokine bead array., Results: Findings showed that 85.3% (127/149) of TNBC cases were positive for either MSLN or NCL, or both; with single positivity rates for MSLN and NCL of 14.1% and 28.9%, respectively. MSLN and NCL peptides, with high binding affinity for HLA-A*02, were combined and introduced to activated PBMCs from healthy donors. The co-pulsed PBMCs significantly induced TEM and TEMRA CD3+ /CD8+ T cells and IFN-γ production, compared to single-peptide pulsed or unpulsed conditions. Notably, MSLN/NCL-specific T cells successfully induced cell death in MSLN+ /NCL+ MDA-MB-231 cells, releasing key cytotoxic factors such as perforin, granzymes A and B, Fas ligand, IFN-γ, and granulysin., Conclusions: These findings serve as a proof-of-concept for using multiple immunogenic peptides as a novel therapeutic approach in TNBC patients., (© 2024. The Author(s).)- Published
- 2024
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