Journal Article Epublish
PubMed: 42524378 DOI: 10.7150/ijbs.132389
HLA class I-specific nucleolin peptides induce therapeutic T cells in triple-negative breast cancer patients.
Int J Biol Sci 22(12):6814-6835
Authors: Suyanee Thongchot, Niphat Jirapongwattana, Thaweesak Chieochansin, Jaturawitt Prasopsiri, Wannasiri Chiraphapphaiboon, Piriya Luangwattananun, Thanyada Rungrotmongkol, Kamonpan Sanachai, Nitchakan Darai, Doonyapat Sa-Nguanraksa, Pornchai O-Charoenrat, Peti Thuwajit, Pa-Thai Yenchitsomanus, Chanitra Thuwajit
Affiliations
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 Thailand.
- Siriraj Center of Research Excellence for Cancer Immunotherapy, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 Thailand.
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 Thailand.
- Hematología computacional y genómica (GrHeCo-Xen), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela 15706 Spain.
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330 Thailand.
- Program in Bioinformatics and Computational Biology, College of Interdisciplinary and Integrative Studies, Chulalongkorn University, Bangkok 10330 Thailand.
- Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002 Thailand.
- Futuristic Science Research Center, School of Science, Walailak University, Nakhon Si Thammarat 80160 Thailand.
- Research Center for Theoretical Simulation and Applied Research in Bioscience and Sensing, Walailak University, Thasala, Nakhon Si Thammarat 80160 Thailand.
- Division of Head-Neck and Breast Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 Thailand.
- Breast Center, MedPark Hospital, Bangkok 10110 Thailand.
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited treatment options owing to the lack of expression of common therapeutic targets such as hormone receptors and HER2. Recent advances in immunopeptidomics have enabled the identification of tumor-associated antigen peptides that can elicit tumor-specific immune responses. We identified four novel HLA class I-restricted peptides derived from nucleolin (NCL), a protein overexpressed in TNBC that is associated with poor outcomes. We predicted and validated pNCL-01 through pNCL-04 because of its strong binding affinity to common HLA alleles (A*02:01 and B*15:01), with pNCL-04 demonstrating broad HLA-binding potential across 20 HLA alleles. Peripheral blood mononuclear cells (PBMCs) from both healthy donors and patients with TNBC were pulsed with these peptides, generating NCL-specific CD8 + T cells that effectively targeted and killed NCL +/PD-L1 + TNBC cell lines in vitro (MDA-MB-231 and HCC70). These T cells exhibited robust IFN-γ secretion and expressed effector memory markers (CD107a), particularly in cancer tissues of patients with high NCL expression. Notably, pNCL-04 functioned as a shared immunogenic peptide, activating T cells in the majority of TNBC patients (7/10) which was predicted to bind up to 20 different HLA class I alleles, supporting its use as a broadly applicable immunogenic peptide. Furthermore, the combination of NCL-specific T cells with atezolizumab enhanced anti-tumor activity, suggesting the potential benefit of combining NCL-targeted immunotherapy with immune checkpoint blockade. In conclusion, this study demonstrates the potential of HLA-restricted NCL peptides in combination with atezolizumab as a rational peptide-based therapeutic strategy for clinical translation in TNBC patients with high NCL.
MeSH
Cells, Triple Negative Breast Neoplasms, Breast Neoplasms, Biological Science Disciplines, Neoplasms, Immunotherapy, Breast, Alleles, Therapeutics