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. 2021 May 1;22(5):1495-1506.
doi: 10.31557/APJCP.2021.22.5.1495.

Reverse Vaccinology Approach in Constructing a Multi-Epitope Vaccine Against Cancer-Testis Antigens Expressed in Non-Small Cell Lung Cancer

Leana Rich M Herrera  1
Affiliations

Reverse Vaccinology Approach in Constructing a Multi-Epitope Vaccine Against Cancer-Testis Antigens Expressed in Non-Small Cell Lung Cancer

Leana Rich M Herrera. Asian Pac J Cancer Prev. .

Abstract

Background: The 5-year survival rate of non-small cell lung cancer (NSCLC) patients has not significantly improved despite advancements in the currently applied treatments. Thus, efforts are put forth in developing novel immunotherapeutic agents targeting cancer-testis antigens (CTA) in NSCLC. This work utilized reverse vaccinology approach in designing a novel multi-epitope vaccine targeting melanoma-associated antigen 3 (MAGEA3), MAGEA4, New York esophageal squamous cell carcinoma-1 (NY-ESO-1), and Kita-Kyushu lung cancer antigen 1 (KK-LC1), being the most frequently expressed CTAs in NSCLC.

Methods: Epitopes were mapped from the sequences of CTAs. The population coverage (PC) of identified CD4+ and CD8+ epitopes were estimated. Candidate linear B cell (BL), CD4+, and CD8+ epitopes were adjoined in a multi-epitope construct (Mvax) with flagellin domain as an adjuvant. Antigenicity, and cross-reactivity of Mvax were examined. The tertiary structure of Mvax was modelled, and validated. All epitopes included in the vaccine were docked with their human leukocyte antigen (HLA) binders. The immunogenicity of epitopes in Mvax was validated through molecular dynamics analysis.

Results: Mvax contains 22 epitopes from MAGEA3, MAGEA4, NY-ESO-1, and KK-LC1. It is classified as antigenic, non-allergen, non-toxic, and possesses physicochemical stability. Epitopes have no significant hits with other human proteins, except for 2 other CTAs frequently expressed in NSCLC. The stretch of BL epitopes in Mvax confers flexibility, and accessibility emphasizing its antigenicity. The tertiary structure analysis showed that Mvax model has good structural quality. All epitopes included in the vaccine are highly immunogenic as indicated by favorable binding affinity, low binding energy, and acceptable root-mean-square deviation (RMSD). CD4+ and CD8+ epitopes have global PC of 81.81%, and 84.15%, respectively.

Conclusion: Overall, in silico evaluations show that Mvax is a potential immunotherapeutic agent against NSCLC.

Keywords: In Silico; Keywords: NSCLC; cancer-testis antigen; reverse vaccinology.

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Conflict of interest statement

Author has no conflict of interest to declare.

Figures

Figure 1
Figure 1
Diagrammatic Presentation of Mvax Construct
Figure 2
Figure 2
Disordered and Solvent-Accessible Residues in Mvax
Figure 3
Figure 3
Mvax Tertiary Structure Model (A) viewed in Pymol, and z-score plots for unrefined (B) and refined structures (C)
Figure 4
Figure 4
Epitope-HLA Docked Structures Viewed in iCn3D. CD4+ (P1-P12) and CD8+ (P13-P19) Epitopes (Yellow) are Docked within the Binding Pockets of HLA Heterodimer Structures (in Purple and Blue)
Figure 5
Figure 5
RMSD Residue Plot of Epitope-HLA Docked Structures P1-P8
Figure 5
Figure 5
RMSD Residue Plot of Epitope-HLA Docked Structures P9-P16
Figure 5
Figure 5
RMSD Residue Plot of Epitope-HLA Docked Structures P17-P19
See this image and copyright information in PMC

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