In-Silico Design of a PIN1/ABCC5-Targeted Multi-Epitope Vaccine for Nasopharyngeal Cancer
Keywords:
ABCC5 (MRP5), Cytotoxic T-cell / helper T-cells, Human leukocyte antigen (HLA) population coverage (Indonesia), Multi-epitope peptide-based vaccine, Nasopharyngeal carcinoma (NPC), PIN1 (peptidyl-prolyl isomerase), Toll-like receptors
Abstract
Nasopharyngeal Carcinoma (NPC) is a rare malignancy. However, it is the fourth most common cancer affecting both sexes in Indonesia, and research on NPC remains limited. NPC is related to Epstein-Barr Virus (EBV) infection, making it a potential target for immunotherapy strategies. Developing a multi-epitope-based NPC vaccine targeting tumor-overexpressed antigens may evoke an immune response against cancer cells and benefit patients with advanced cancer stages or those resistant to treatment. Four cytotoxic (CTL) and one helper T-cell (HTL) epitopes from PIN1 were identified using NetMHCpan and NetMHCIIpan algorithms, respectively. Whereas from ABCC5, five CTL and four HTL epitopes were identified using the same algorithms. These epitopes were found to have good coverage across the Indonesian population, with population coverage analysis showing 99% coverage for human leukocyte antigen (HLA) Class I and 95% for HLA Class II. Having fulfilled other criteria such as immunogenicity, IFN-γ-inducing ability, and non-homology to human peptides, the epitopes were assembled into a vaccine construct together with E. coli and Bacillus as adjuvants and appropriate linkers. The construct was shown to have good physicochemical characteristics and the ability to induce CTL and HTL responses, which stem from the engagement of the vaccine with toll-like receptor 4 (TLR4) as revealed by docking simulations.
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References
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Janeway, T. P. (2001). Immunobiology: The Immune System in Health and Disease. New York: Garland Science. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK27156/
Kamta, C. M. (2017). Advancing cancer therapy with present and emerging immunooncology approaches. Frontiers in oncology, 7, 64. https://doi.org/10.3389/fonc.2017.00064
Kavoosi, C. A. (2007). Strategy for selecting and characterizing linker peptides for CBM9-tagged fusion proteins expressed in Escherichia coli. Biotechnology and bioengineering, 98(3), 599–610. https://doi.org/10.1002/bit.21396
Lins, T. A., & Brasseur, R. (2003). Analysis of accessible surface of residues in proteins. Protein Science. Retrieved from https://doi.org/10.1110/ps.0304803
Lonez, C., Irvine, K. L., Pizzuto, M., Schmidt, B. I., Gay, N. J., Ruysschaert, J. M., . . . Bryant, C. E. (2015). Critical residues involved in Toll-like receptor 4 activation by cationic lipid nanocarriers are not located at the lipopolysaccharide-binding interface. Cell Mol Life Sci. doi:10.1007/s00018-015-1915-1
Malonis, R. J., Lai, J. R., & Vergnolle, O. (2019, December). Peptide-Based Vaccines: Current Progress and Future Challenges. Chem. Rev. Retrieved from https://doi.org/10.1021/acs.chemrev.9b00472
Melief, v. H., & van der Burg. (2015). Therapeutic cancer vaccines. Journal of Clinical Investigation, 125, 3401-3412. https://doi.org/10.1172/JCI80009
Naveed, M., Sheraz, M., Amin, A., Waseem, M., Aziz, T., Khan, A. A., . . . & Alhomrani, M. (2021). Designing a Novel Peptide-Based Multi-Epitope Vaccine to Evoke a Robust Immune Response against Pathogenic Multidrug-Resistant Providencia heimbachae. Vaccines. Retrieved from https://doi.org/10.3390/vaccines10081300
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Oblak, R. (2011). Toll-Like Receptor 4 Activation in Cancer Progression and Therapy. Journal of Immunology Research. Retrieved from https://doi.org/10.1155/2011/609579
Oliveira Tosta, S. F. (2019). Multi-epitope based vaccine against yellow fever virus applying immunoinformatics approaches. J. Biomol. Struct. Dyn. Retrieved from https://doi.org/10.1080/07391102.2019.1707120
Panina-Bordignon, P. e. (1989). Universally immunogenic T cell epitopes: Promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur. J. Immunol. Retrieved from https://doi.org/10.1002/eji.1830191209
Reynisson, B., Alvarez, B., Paul, S., Peters, B., & Nielsen, M. (2020). NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Research, 48, 449-454. Retrieved from https://doi.org/10.1093/nar/gkaa379
Rosales-Mendoza, S., & Angulo, C. (2015). Bacillus subtilis comes of age as a vaccine production host and delivery vehicle. Expert Review of Vaccines. doi:10.1586/14760584.2015.1051469
S. S., D. U., & & Yao, K. T. (2008). Expression of ATP-binding cassette transporter genes in nasopharyngeal carcinoma. Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 28, 449–452. https://pubmed.ncbi.nlm.nih.gov/18359711/
Sinha S, G. A. (2021, July). Nasopharyngeal Cancer. Treasure, Island, FL: StatPearls Publishing. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK459256/
Taylor, G. S., & & Steven, N. M. (2016). Therapeutic vaccination strategies to treat nasopharyngeal carcinoma. Chinese clinical oncology. Retrieved from https://doi.org/10.21037/cco.2016.03.20
Testa, R. (2012). Role of T-cell epitope-based vaccine in prophylactic and therapeutic applications. Future Virol. Retrieved from https://doi.org/10.2217/fvl.12.108
Turk, W. J.-P. (2002). Multiple pathways to tumor immunity and concomitant autoimmunity. Immunol Rev., 188, 122–135. https://doi.org/10.1034/j.1600-065x.2002.18811.x
Vaure, Y. A. (2014). comparative review of toll-like receptor 4 expression and functionality in different animal species. Front. Immunol., 5. 316. https://doi.org/10.3389/fimmu.2014.00316
Xu, M., Cheung, C. C.-M., Chow, C., Lun, S. W.-M., Cheung, S.-T., & Lo, K.-W. (2016). Overexpression of PIN1 Enhances Cancer Growth and Aggressiveness with Cyclin D1 Induction in EBV-Associated Nasopharyngeal Carcinoma. . PLoS ONE 11(6): e0156833. Retrieved from https://doi.org/10.1371/journal.pone.0156833
Yuliwulandari, R., Kashiwase, K., Nakajima, H., & Uddin, J. (2009). Polymorphisms of HLA genes in Western Javanese (Indonesia): Close affinities to Southeast Asian populations. Tissue Antigens, 73, 46-53. doi:10.1111/j.1399-0039.2008.01178.x
Akazawa, T., Masuda, H., Saeki, Y., Matsumoto, M., Takeda, K., Tsujimura, K., . . . Seya, T. (2004). Adjuvant-mediated tumor regression and tumor-specific cytotoxic response are impaired in MyD88-deficient mice. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-03-1518
Borst, d. W., & van de Wetering K. (2007). Multidrug resistance-associated proteins 3, 4, and 5. Pflügers ArchPflügers Arch., 661-673. https://doi.org/10.1007/s00424-006-0054-9
Carty, A. G. (2010). Recent insights into the role of Toll-like receptors in viral infection. Clin. Exp. Immunol. https://doi.org/10.1111/j.1365-2249.2010.04196.x
Chandra, S., & Singh, T. R. (2012). Linear B cell epitope prediction for epitope vaccine design against meningococcal disease and their computational validations through physicochemical properties. Netw Model Anal Health Inform Bioinforma, 1, 153-159. Retrieved from https://doi.org/10.1007/s13721-012-0019-1
Chauhan, R. T. (2019). Designing a multi-epitope based vaccine to combat Kaposi Sarcoma utilizing immunoinformatics approach. Sci Rep, 1-15. https://doi.org/10.1038/s41598-019-39299-8
Chen, Y., Wu, Y., & Yang, H. e. (2018). Prolyl isomerase Pin1: a promoter of cancer and a target for therapy. Cell Death Dis, 9. Retrieved from https://doi.org/10.1038/s41419-018-0844-y
Davies, D. R. (2007). Harnessing bioinformatics to discover new vaccines. Drug Discov. Today. https://doi.org/10.1016/j.drudis.2007.03.010
Delves, P. J., & Roitt, I. M. (2000). The immune system. First of two parts. The New England journal of medicine, 343(1), 37–49. https://doi.org/10.1056/NEJM200007063430107
Dhanda, e. a. (2013). Designing of interferon-gamma inducing MHC class-2 binders. Biology Direct. Retrieved from http://crdd.osdd.net/raghava/ifnepitope/index.php
Doherty, A. W. (1992). Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annu. Rev. Immunol. Retrieved from https://doi.org/10.1146/annurev.iy.10.040192.001011.
Eldridge, G. R., Hughey, H., Rosenberger, L., Martin, S. M., Shapiro, A. M., D'Antonio, E., . . . & Starks, C. M. (2021). Safety and immunogenicity of an adjuvanted Escherichia coli adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study. Human vaccines & immunotherapeutics. Retrieved from https://doi.org/10.1080/21645515.2020.1834807
Fleri, W., Paul, S., Dhanda, S. K., Mahajan, S., Xu, X., Peters, B., & Sette, A. (2017, March). The Immune Epitope Database and Analysis Resource in Epitope Discovery and Synthetic Vaccine Design. Front Immunol. https://doi.org/10.3389/fimmu.2017.00278
Flower, D., Doytchinova, I., Zaharieve, N., & Dimitrov, I. (2017). Immunogenicity Prediction by VaxiJen: A Ten-Year Overview. Journal of Proteomics & Bioinformatics. doi:10. 10.4172/jpb.1000454
Fonseca, C., & & Dranoff, G. (2008). Capitalizing on the immunogenicity of dying tumor cells. Clinical cancer research: an official journal of the American Association for Cancer Research, 14(6), 1603–1608. https://doi.org/10.1158/1078-0432.CCR-07-2245
Galanis, K. A., Nastou, K. C., Papandreou, N. C., Petichakis, G. N., Pigis, D. G., & & Iconomidou, V. A. (2021). Linear B-Cell Epitope Prediction for In Silico Vaccine Design: A Performance Review of Methods. . International journal of molecular sciences. Retrieved from https://doi.org/10.3390/ijms22063210
Gondhowiarjo, S., Meidania, L., Senoaji, F., & Sekarutami, S. M. (2019). Nasopharyngeal Carcinoma Profile in dr. Cipto Mangunkusumo Hospital Year 2013. Journal of the Indonesian Radiation Oncology Society. Retrieved from http://www.pori.or.id/journal/index.php/JORI/article/download/98/82
Hossain, M.S., Hossan, M.I., Mizan, S., Moin, A.T., Yasmin, F., Akash, A.-S., Powshi, S.N., Hasan, A.K.R., Chowdhury, A.S. (2021) Immunoinformatics Approach to Designing a Multi-Epitope Vaccine against Saint Louis Encephalitis Virus. Inform. Med. Unlocked, 22, 100500 https://doi.org/10.1016/j.imu.2020.100500
Hou, Y., Zhu, Q., Li, Z., Peng, Y., Yu, X., Yuan, B., . . . & Li, X. (2017). The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells. Cell death & disease, 8. Retrieved from https://doi.org/10.1038/cddis.2017.53
Janeway, T. P. (2001). Immunobiology: The Immune System in Health and Disease. New York: Garland Science. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK27156/
Kamta, C. M. (2017). Advancing cancer therapy with present and emerging immunooncology approaches. Frontiers in oncology, 7, 64. https://doi.org/10.3389/fonc.2017.00064
Kavoosi, C. A. (2007). Strategy for selecting and characterizing linker peptides for CBM9-tagged fusion proteins expressed in Escherichia coli. Biotechnology and bioengineering, 98(3), 599–610. https://doi.org/10.1002/bit.21396
Lins, T. A., & Brasseur, R. (2003). Analysis of accessible surface of residues in proteins. Protein Science. Retrieved from https://doi.org/10.1110/ps.0304803
Lonez, C., Irvine, K. L., Pizzuto, M., Schmidt, B. I., Gay, N. J., Ruysschaert, J. M., . . . Bryant, C. E. (2015). Critical residues involved in Toll-like receptor 4 activation by cationic lipid nanocarriers are not located at the lipopolysaccharide-binding interface. Cell Mol Life Sci. doi:10.1007/s00018-015-1915-1
Malonis, R. J., Lai, J. R., & Vergnolle, O. (2019, December). Peptide-Based Vaccines: Current Progress and Future Challenges. Chem. Rev. Retrieved from https://doi.org/10.1021/acs.chemrev.9b00472
Melief, v. H., & van der Burg. (2015). Therapeutic cancer vaccines. Journal of Clinical Investigation, 125, 3401-3412. https://doi.org/10.1172/JCI80009
Naveed, M., Sheraz, M., Amin, A., Waseem, M., Aziz, T., Khan, A. A., . . . & Alhomrani, M. (2021). Designing a Novel Peptide-Based Multi-Epitope Vaccine to Evoke a Robust Immune Response against Pathogenic Multidrug-Resistant Providencia heimbachae. Vaccines. Retrieved from https://doi.org/10.3390/vaccines10081300
Nevagi, R. J., Toth, I., & Skwarczynski, M. (2018, November). 12 - Peptide-based vaccines. (S. Koutsopoulos, Ed.) The University of Queensland, Brisbane, QLD, Australia: Woodhead Publishing. Retrieved from https://www.sciencedirect.com/science/article/pii/B9780081007365000120?via=ihub
Nielsen, M. (2022). Retrieved from https://services.healthtech.dtu.dk/service.php?NetMHC-4.0
Oblak, R. (2011). Toll-Like Receptor 4 Activation in Cancer Progression and Therapy. Journal of Immunology Research. Retrieved from https://doi.org/10.1155/2011/609579
Oliveira Tosta, S. F. (2019). Multi-epitope based vaccine against yellow fever virus applying immunoinformatics approaches. J. Biomol. Struct. Dyn. Retrieved from https://doi.org/10.1080/07391102.2019.1707120
Panina-Bordignon, P. e. (1989). Universally immunogenic T cell epitopes: Promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur. J. Immunol. Retrieved from https://doi.org/10.1002/eji.1830191209
Reynisson, B., Alvarez, B., Paul, S., Peters, B., & Nielsen, M. (2020). NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Research, 48, 449-454. Retrieved from https://doi.org/10.1093/nar/gkaa379
Rosales-Mendoza, S., & Angulo, C. (2015). Bacillus subtilis comes of age as a vaccine production host and delivery vehicle. Expert Review of Vaccines. doi:10.1586/14760584.2015.1051469
S. S., D. U., & & Yao, K. T. (2008). Expression of ATP-binding cassette transporter genes in nasopharyngeal carcinoma. Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 28, 449–452. https://pubmed.ncbi.nlm.nih.gov/18359711/
Sinha S, G. A. (2021, July). Nasopharyngeal Cancer. Treasure, Island, FL: StatPearls Publishing. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK459256/
Taylor, G. S., & & Steven, N. M. (2016). Therapeutic vaccination strategies to treat nasopharyngeal carcinoma. Chinese clinical oncology. Retrieved from https://doi.org/10.21037/cco.2016.03.20
Testa, R. (2012). Role of T-cell epitope-based vaccine in prophylactic and therapeutic applications. Future Virol. Retrieved from https://doi.org/10.2217/fvl.12.108
Turk, W. J.-P. (2002). Multiple pathways to tumor immunity and concomitant autoimmunity. Immunol Rev., 188, 122–135. https://doi.org/10.1034/j.1600-065x.2002.18811.x
Vaure, Y. A. (2014). comparative review of toll-like receptor 4 expression and functionality in different animal species. Front. Immunol., 5. 316. https://doi.org/10.3389/fimmu.2014.00316
Xu, M., Cheung, C. C.-M., Chow, C., Lun, S. W.-M., Cheung, S.-T., & Lo, K.-W. (2016). Overexpression of PIN1 Enhances Cancer Growth and Aggressiveness with Cyclin D1 Induction in EBV-Associated Nasopharyngeal Carcinoma. . PLoS ONE 11(6): e0156833. Retrieved from https://doi.org/10.1371/journal.pone.0156833
Yuliwulandari, R., Kashiwase, K., Nakajima, H., & Uddin, J. (2009). Polymorphisms of HLA genes in Western Javanese (Indonesia): Close affinities to Southeast Asian populations. Tissue Antigens, 73, 46-53. doi:10.1111/j.1399-0039.2008.01178.x
Published
2026-03-31
How to Cite
Ashiila, P., & Gustiananda, M. (2026). In-Silico Design of a PIN1/ABCC5-Targeted Multi-Epitope Vaccine for Nasopharyngeal Cancer. Indonesian Journal of Life Sciences, 8(01), 41-78. https://doi.org/https://doi.org/10.54250/ijls.v8i01.218
Issue
Section
Biotechnology
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