Design of a new multi-epitope peptide vaccine for non-small cell Lung cancer via vaccinology methods: an in silico study

Document Type : Original article

Authors

1 Department of Mycology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

2 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

3 Department of Microbiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran

4 Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

5 Department of Laboratory Sciences, Sirjan School of Medical Sciences, Sirjan, Iran

6 Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran

Abstract

Lung cancer is the most common type of tumor worldwide. Non-small-cell lung carcinoma (NSCLC) is considered any epithelial cell-related lung cancer, which includes more than 85% of all lung cancer cases. NSCLC is less responsive to chemotherapy than SCLC. Therefore, the need for other treatments has become more pronounced and immunotherapy has gained increasing attention as a promising therapy in recent years. The current study aimed to design a multi-epitope peptide vaccine targeting main cancer/testis antigens of SP17, AKAP4, and PTTG1, which have a major function in tumor cell proliferation invasion. The protein vaccine was constructed using the rigorous immunoinformatics analysis and investigation of several immune system parameters, considering B cell epitopes and CD4 and CD8 induced epitopes as the most important cells to respond to cancer cells. Inverse translation and optimization of codons were performed to have the designed protein's cloning as well as expression potential in E.coli. Physicochemical, antigenic, and allergenic features were assessed to confirm the safety and immunogenicity of the vaccine. The secondary and tertiary structures were predicted. Finally, intrinsic disorder and 3D model refinement and validation were performed to eliminate structural problems. The designed construct had a stable structure that could be an antigen and stimulate the immune system and not be an allergen. The built model 3D structure was valid and stable. Further investigations are needed to approve the safety and immunogenic property of this new vaccine for NSCLC before it can be used in patients.

Keywords


  1. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for African Americans, 2019. CA Cancer J Clin 2019;69:211-233.
  2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
  3. Group N-sCLCC. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899-909.
  4. Scott WJ, Howington J, Feigenberg S, Movsas B, Pisters K. Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines. Chest 2007;132:234S-242S.
  5. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Angelo Burgio M,  Fayette J,  Lena H, Poddubskaya E,  Gerber DE,  Gettinger SN,  Rudin CM,  Rizvi N, Crinò L,  Blumenschein Jr GR,  Antonia SJ, Dorange C,  Harbison CT, Friedrich Graf F,  Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 2015;373:1627-1639.
  6. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-264.
  7. Butts C, Maksymiuk A, Goss G, Soulieres D, Marshall E, Cormier Y, Ellis PM, Price A, Sawhney R, Beier F, Falk M, Murray N. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. J Cancer Res Clin Oncol 2011;137:1337-1342.
  8. Taheri-Anganeh M, Amiri A, Movahedpour A, Khatami SH, Ghasemi Y, Savardashtaki A, Mostafavi-Pour Z. In silico evaluation of PLAC1-fliC as a chimeric vaccine against breast cancer. Iran Biomed J 2020;24:173-182.
  9. Vafadar A, Taheri-Anganeh M, Movahedpour A, Jamali Z, Irajie C, Ghasemi Y, Savardashtaki A. In silico design and evaluation of scFv-CdtB as a novel immunotoxin for breast cancer treatment. Inter J Cancer Manag 2020;13.
  10. Taheri-Anganeh M, Savardashtaki A, Vafadar A, Movahedpour A, Shabaninejad Z, Maleksabet A, Amiri A, Ghasemi Y, Irajie C. In Silico Design and Evaluation of PRAME+ FliCΔD2D3 as a New Breast Cancer Vaccine Candidate. Iran J Med Sci 2021;46:52-60.
  11. Samavarchi Tehrani S, Gharibi S, Movahedpour A, Goodarzi G, Jamali Z, Khatami SH, Maniati M, Ranjbar M, Shabaninejad Z, Savardashtaki A, Taheri-Anganeh M. Design and evaluation of scFv-RTX-A as a novel immunotoxin for breast cancer treatment: an in silico approach. J Immunoassay Immunochem 2021;42:19-33.
  12. Oliveres H, Caglevic C, Passiglia F, Taverna S, Smits E, Rolfo C. Vaccine and immune cell therapy in non-small cell lung cancer. J Thorac Dis 2018;10(Suppl 13):S1602-S1614.
  13. Mirandola L, Figueroa JA, Phan TT, Grizzi F, Kim M, Rahman RL, Jenkins MR, Cobos E, Jumper C, Alalawi R, Chiriva-Internati M. Novel antigens in non-small cell lung cancer: SP17, AKAP4, and PTTG1 are potential immunotherapeutic targets. Oncotarget 2015;6: 2812-2826.
  14. Djureinovic D, Dodig-Crnković T, Hellström C, Holgersson G, Bergqvist M, Mattsson JS, Ponten F, Stahle E, Schwenk JM, Micke P. Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer. Lung Cancer 2018;125:157-163.
  15. Zhang L. Multi-epitope vaccines: a promising strategy against tumors and viral infections. Cell Mol Immunol 2018;15:182-184.
  16. Gumireddy K, Li A, Chang DH, Liu Q, Kossenkov AV, Yan J, Korst RJ, Nam BT, Xu H, Zhang L, Ganepola G, Showe LC, Huang Q. AKAP4 is a circulating biomarker for non-small cell lung cancer. Oncotarget 2015;6:17637-17647.
  17. Shepherd FA, Douillard JY, Blumenschein Jr GR. Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. J Thorac Oncol 2011;6:1763-1773.
  18. Mellstedt H, Vansteenkiste J, Thatcher N. Vaccines for the treatment of non-small cell lung cancer: investigational approaches and clinical experience. Lung Cancer 2011;73:11-17.
  19. Bilusic M, Madan RA. Therapeutic cancer vaccines: the latest advancement in targeted therapy. Am J Ther 2012;19:e172-e181.
  20. Tourani M, Karkhah A, Najafi A. Development of an epitope-based vaccine inhibiting immune cells rolling and migration against atherosclerosis using in silico approaches. Comput Biol Chem 2017;70:156-163.
  21. Yousefi T, Mir SM, Asadi J, Tourani M, Karimian A, Maniati M, Samavarchi Tehrani S. In silico analysis of non-synonymous single nucleotide polymorphism in a human KLK-2 gene associated with prostate cancer. Meta Gene 2019;21:100578.
  22. Vita R, Mahajan S, Overton JA, Dhanda SK, Martini S, Cantrell JR, Wheeler DK, Sette A, Peters B. The immune epitope database (IEDB): 2018 update. Nucleic Acids Res 2019;47(D1):D339-D343.
  23. Ponomarenko J, Bui HH, Li W, Fusseder N, Bourne PE, Sette A, Peters B. ElliPro: a new structure-based tool for the prediction of antibody epitopes. BMC Bioinformatics 2008;9: 514.
  24. Haste Andersen P, Nielsen M, Lund O. Prediction of residues in discontinuous B-cell epitopes using protein 3D structures. Protein Sci 2006;15:2558-2567.
  25. McGuffin LJ, Bryson K, Jones DT. The PSIPRED protein structure prediction server. Bioinformatics 2000;16:404-405.
  26. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015;10:845-858.
  27. Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat protocols. 2010;5:725-738.
  28. Suckow MA. Cancer vaccines: harnessing the potential of anti-tumor immunity. Vet J 2013;198:28-33.
  29. Taheri-Anganeh M, Khatami SH, Jamali Z, Savardashtaki A, Ghasemi Y, Mostafavi-Pour Z. In silico analysis of suitable signal peptides for secretion of a recombinant alcohol dehydrogenase with a key role in atorvastatin enzymatic synthesis. Mol Biol Res Commun 2019;8:17-26.
  30. Taheri-Anganeh M, Khatami SH, Jamali Z, Movahedpour A, Ghasemi Y, Savardashtaki A, Mostafavi-Pour Z. LytU-SH3b fusion protein as a novel and efficient enzybiotic against methicillin-resistant Staphylococcus aureus. Mol Biol Res Commun 2019;8:151-158.
  31. Khatami SH, Taheri-Anganeh M, Arianfar F, Savardashtaki A, Sarkari B, Ghasemi Y, Mostafavi-Pour Z. Analyzing signal peptides for secretory production of recombinant diagnostic antigen B8/1 from Echinococcus granulosus: An in silico approach. Mol Biol Res Commun 2020;9:1-10.
  32. Jamali Z, Taheri-Anganeh M, Entezam M. Prediction of potential deleterious nonsynonymous single nucleotide polymorphisms of HIF1A gene: A computational approach. Comput Biol Chem 2020;88:107354.
  33. Khatami SH, Taheri-Anganeh M, Movahedpour A, Savardashtaki A, Ramezani A, Sarkari B, Mostafavi-Pour Z. Serodiagnosis of human cystic echinococcosis based on recombinant antigens B8/1 and B8/2 of Echinococcus granulosus. J Immunoassay Immunochem 2020; 41:1010-1020.
  34. Tehrani SS, Goodarzi G, Naghizadeh M, Khatami SH, Movahedpour A, Abbasi A, Shabaninejad Z, Khalaf N, Taheri-Anganeh M, Savardashtaki A. Suitable signal peptides for secretory production of recombinant granulocyte colony stimulating factor in Escherichia coli. Recent Pat Biotechnol 2020;14:269-282.
  35. Shahsavani N, Sheikhha MH, Yousefi H, Sefid F. In silico homology modeling and epitope prediction of NadA as a potential vaccine candidate in Neisseria meningitidis. Int J Mol Cell Med 2018;7:53-68.
  36. Validi M, Karkhah A, Prajapati VK, Nouri HR. Immuno-informatics based approaches to design a novel multi epitope-based vaccine for immune response reinforcement against Leptospirosis. Mol Immunol 2018;104:128-138.
  37. Nezafat N, Ghasemi Y, Javadi G, Khoshnoud MJ, Omidinia E. A novel multi-epitope peptide vaccine against cancer: an in silico approach. J Theor Biol 2014;349:121-134.
  38. Paucek RD, Baltimore D, Li G. The cellular immunotherapy revolution: arming the immune system for precision therapy. Trends Immunol 2019;40:292-309.
  39. Zheng W, Zhang C, Bell EW, Zhang Y. I-TASSER gateway: A protein structure and function prediction server powered by XSEDE. Future Gener Comput Syst 2019;99:73-85.
  40. Goleij Z, Hosseini HM, Amin M, Amani J, Behzadi E, Imani Fooladi AA. In silico evaluation of two Targeted Chimeric Proteins Based on Bacterial Toxins for Breast Cancer Therapy. Inter J Cancer Manag 2019;12:e83315.
  41. Junkins RD, Gallovic MD, Johnson BM, Collier MA, Watkins-Schulz R, Cheng N, David CN, McGee CE, Sempowski GD, Shterev I, McKinnon K, Bachelder EM, Ainslie KM, Ting JPY. A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination. J Control Release 2018;270:1-13.
  42. Yuen GJ, Demissie E, Pillai S. B lymphocytes and cancer: a love–hate relationship. Trends Cancer 2016;2:747-757.
  43. Berzofsky JA, Terabe M, Trepel JB, Pastan I, Stroncek DF, Morris JC, Wood LV. Cancer vaccine strategies: translation from mice to human clinical trials. Cancer Immunol Immunother 2018;67:1863-1869.