Conjugation with S4 Protein Transduction Domain Enhances the Immunogenicity of the Peptide Vaccine Against Breast Cancer

Overview

Journal Mol Clin Oncol

Date 2025 Jan 8

PMID 39776941

Authors

Jayla A Moore

Umer Ali

Sunitha Vungarala

Artenzia Young-Seigler

Venkataswarup Tiriveedhi

Affiliations

Soon will be listed here.

Abstract

Although peptide vaccines offer a novel venue for cancer immunotherapy, clinical success has been rather limited. Cell-penetrating peptides, due to their ability to translocate through the cell membrane, could be conjugated to the peptide vaccine to2 enhance therapeutic efficiency. The S4 transduction domain of the shaker-potassium channel was conjugated to mammaglobin-A (MamA) immunodominant epitope (MamA2.1) to verify its anticancer immunogenicity. S4-MamA2.1 peptide has demonstrated significantly higher epitope loading and stable membrane expression of HLA-A2 antigen-presenting molecules on T2 cell lines. Further, these S4-MamA2.1 treated T2 cells were able to activate naïve CD8 T cells to induce MamA-specific cytotoxicity against breast cancer cells. Conjugation of the S4 domain has also demonstrated a slight increase in immunogenicity of lesser immunodominant MamA epitopes. The conjugation of the S4 domain to N-terminus of MamA2.1 demonstrated significantly higher immunogenicity over C-terminus conjugation. Taken together, the results of the present study suggest that conjugation of the S4 cell-penetrating peptide domain to MamA2.1 epitope enhances the peptide vaccine immunogenicity against MamA-expressing breast cancers.

References

Tiriveedhi V, Miller M, Butko P, Li M . Autonomous transmembrane segment S4 of the voltage sensor domain partitions into the lipid membrane. Biochim Biophys Acta. 2012; 1818(7):1698-705. PMC: 3412939. DOI: 10.1016/j.bbamem.2012.03.011. View

Luft T, Rizkalla M, Tai T, Chen Q, MacFarlan R, Davis I . Exogenous peptides presented by transporter associated with antigen processing (TAP)-deficient and TAP-competent cells: intracellular loading and kinetics of presentation. J Immunol. 2001; 167(5):2529-37. DOI: 10.4049/jimmunol.167.5.2529. View

Tiriveedhi V, Ivy M, Myles E, Zent R, Rathmell J, Titze J . Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response. Cancers (Basel). 2021; 13(7. PMC: 8038238. DOI: 10.3390/cancers13071690. View

OBrien N, Maguire T, ODonovan N, Lynch N, Hill A, McDermott E . Mammaglobin a: a promising marker for breast cancer. Clin Chem. 2002; 48(8):1362-4. View

Milosevic B, Stojanovic B, Cvetkovic A, Jovanovic I, Spasic M, Dimitrijevic Stojanovic M . The Enigma of Mammaglobin: Redefining the Biomarker Paradigm in Breast Carcinoma. Int J Mol Sci. 2023; 24(17). PMC: 10487666. DOI: 10.3390/ijms241713407. View

Curigliano G, Bagnardi V, Ghioni M, Louahed J, Brichard V, Lehmann F . Expression of tumor-associated antigens in breast cancer subtypes. Breast. 2019; 49:202-209. PMC: 7375652. DOI: 10.1016/j.breast.2019.12.002. View

Liu Z, Yang X, Duan C, Li J, Tong R, Fan Y . Identification and characterization of mammaglobin-A epitope in heterogenous breast cancers for enhancing tumor-targeting therapy. Signal Transduct Target Ther. 2020; 5(1):82. PMC: 7256037. DOI: 10.1038/s41392-020-0183-1. View

Brufsky A, Kwan M, Sandin R, Stergiopoulos S, Karanth S, Cha-Silva A . Trends in HR+ metastatic breast cancer survival before and after CDK4/6 inhibitor introduction in the United States: a SEER registry analysis of patients with HER2- and HER2+ metastatic breast cancer. Breast Cancer Res Treat. 2024; 208(2):223-235. PMC: 11455714. DOI: 10.1007/s10549-024-07469-6. View

Backlund C, Holden R, Moynihan K, Garafola D, Farquhar C, Mehta N . Cell-penetrating peptides enhance peptide vaccine accumulation and persistence in lymph nodes to drive immunogenicity. Proc Natl Acad Sci U S A. 2022; 119(32):e2204078119. PMC: 9371699. DOI: 10.1073/pnas.2204078119. View

10.

Yang J, Luo Y, Shibu M, Toth I, Skwarczynskia M . Cell-penetrating Peptides: Efficient Vectors for Vaccine Delivery. Curr Drug Deliv. 2019; 16(5):430-443. PMC: 6637094. DOI: 10.2174/1567201816666190123120915. View

11.

Moynihan K, Holden R, Mehta N, Wang C, Karver M, Dinter J . Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability. Cancer Immunol Res. 2018; 6(9):1025-1038. PMC: 6247902. DOI: 10.1158/2326-6066.CIR-17-0607. View

12.

Nguyen A, Szeto C, Gras S . The pockets guide to HLA class I molecules. Biochem Soc Trans. 2021; 49(5):2319-2331. PMC: 8589423. DOI: 10.1042/BST20210410. View

13.

Tiriveedhi V, Butko P . A fluorescence spectroscopy study on the interactions of the TAT-PTD peptide with model lipid membranes. Biochemistry. 2007; 46(12):3888-95. DOI: 10.1021/bi602527t. View

14.

Xie N, Shen G, Gao W, Huang Z, Huang C, Fu L . Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther. 2023; 8(1):9. PMC: 9816309. DOI: 10.1038/s41392-022-01270-x. View

15.

Babaer D, Zheng M, Ivy M, Zent R, Tiriveedhi V . Methylselenol producing selenocompounds enhance the efficiency of mammaglobin-A peptide vaccination against breast cancer cells. Oncol Lett. 2019; 18(6):6891-6898. PMC: 6876340. DOI: 10.3892/ol.2019.11010. View

16.

Tiriveedhi V, Tucker N, Herndon J, Li L, Sturmoski M, Ellis M . Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer. Clin Cancer Res. 2014; 20(23):5964-75. PMC: 4322416. DOI: 10.1158/1078-0432.CCR-14-0059. View

17.

Nelde A, Rammensee H, Walz J . The Peptide Vaccine of the Future. Mol Cell Proteomics. 2021; 20:100022. PMC: 7950068. DOI: 10.1074/mcp.R120.002309. View

18.

Jaramillo A, Narayanan K, Campbell L, Benshoff N, Lybarger L, Hansen T . Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes by CD8+ cytotoxic T lymphocytes from breast cancer patients. Breast Cancer Res Treat. 2004; 88(1):29-41. DOI: 10.1007/s10549-004-8918-1. View

19.

Ding Y, Li Z, Jaklenec A, Hu Q . Vaccine delivery systems toward lymph nodes. Adv Drug Deliv Rev. 2021; 179:113914. PMC: 9418125. DOI: 10.1016/j.addr.2021.113914. View

20.

Sotirov S, Dimitrov I . Tumor-Derived Antigenic Peptides as Potential Cancer Vaccines. Int J Mol Sci. 2024; 25(9). PMC: 11084719. DOI: 10.3390/ijms25094934. View