Neoepitope

Neoepitopes are a class of major histocompatibility complex (MHC) bounded peptides that arise from tumor-specific mutations.[1] They represent the antigenic determinants of neoantigens. Neoepitopes are recognized by the immune system as targets for T cells and can elicit immune response to cancer.[2][3]

Description

Epitopes, also referred to as antigenic determinants, are parts of an antigen that are recognized by the immune system. A neoepitope is an epitope the immune system has not encountered before. Therefore it is not subject to tolerance mechanisms of the immune system.[4] As the mutant gene product is only expressed in tumors and is not found in non-cancerous cells, neoepitopes may evoke a vigorous T cell response.[5]

Neoepitopes arise from post-translational modifications. The mRNA translates information from the DNA into polypeptide composed of 20 standard amino acids and then proteins. Several of the standard amino acids can be posttranslationally modified by enzymatic processes, or can be altered through spontaneous (nonenzymatic) biochemical reactions.[6]

There is increasing evidence that immune recognition of neoepitopes produced by cancer-specific mutations is a key mechanism for the induction of immune-mediated tumor rejection. Opportunities for therapeutic targeting of cancer specific neoepitopes are under investigation.[7]

Neoepitopes as target for immunotherapy

Cancer is a patient-specific disease, and no two tumors are alike. Thus, the immunogenicity of each tumor is unique.[8] A novel strategy against cancer is epitope selection for mutanome-directed individualized cancer immunotherapy.[4]

Individualized cancer immunotherapy leverages the adaptive immune system by targeting T cells to tumor cells that have a tumor specific mutant antigen (neoantigen) with neoepitopes recognized by a receptor on T cells.[9] One challenge is to identify the neoepitopes that trigger a suitable immune response, that is, to find out which neoepitopes in the individual tumor are highly immunogenic.[10]

Cancer vaccines based on neoepitopes

Individualized cancer immunotherapy includes vaccination with tumor mutation-derived neoepitopes. The concept is based on a mapping of the tumor-specific individual mutanome with identification of a range of suitable neoepitopes for a patient-specific vaccine.[11] It is expected that the neoepitopes in the vaccine will trigger T cell responses to the specific cancer. For the concept of individualized cancer vaccination first data are available.[12][13][14][15]

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References
  1. Leclerc, M; Mezquita, L; Guillebot De Nerville, G; Tihy, I; Malencia, I; Chouaib, S; Mami-Chouaib, S (2019). "Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing". Frontiers in Immunology. 10: 1505. doi:10.3389/fimmu.2019.01505. PMC 6616108. PMID 31333652.
  2. Vormehr, M; Diken, M; Boegel, S; Kreiter, S; Türeci, Ö; Sahin, U (2016). "Mutanome directed cancer immunotherapy". Current Opinion in Immunology. 39: 14–22. doi:10.1016/j.coi.2015.12.001. PMID 26716729.
  3. Katsnelson, A (2016). "Mutations as munitions: Neoantigen vaccines get a closer look as cancer treatment". Nature Medicine. 22 (2): 122–4. doi:10.1038/nm0216-122. PMID 26845402.
  4. Vormehr, M; Türeci, Ö; Sahin, U (2019). "Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines". Annual Review of Medicine. 70: 395–407. doi:10.1146/annurev-med-042617-101816. PMID 30691374.
  5. Heemskerk, B; Kvistborg, P; Schumacher, TNM (2013). "The cancer antigenome". The EMBO Journal. 32 (2): 194–203. doi:10.1038/emboj.2012.333. PMC 3553384. PMID 23258224.
  6. James, EA; Pietropaolo, M; Mamula, MJ (2018). "Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance". Diabetes. 67 (6): 1035–1042. doi:10.2337/dbi17-0030. PMC 5961411. PMID 29784651.
  7. Wilson, EA; Anderson, KS (2018). "Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy". Expert Review of Proteomics. 15 (12): 1065–1077. doi:10.1080/14789450.2018.1545578. PMID 30408427.
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  9. Feng, YY; Griffith, OL; Griffith, M (2017). "Clinical implications of neoepitope landscapes for adult and pediatric cancers". Genome Medicine. 9 (1): 77. doi:10.1186/s13073-017-0470-9. PMC 5577778. PMID 28854952.
  10. Saini, SK; Rekers, H; Hadrup, SR (2017). "Novel tools to assist neoepitope targeting in personalized cancer immunotherapy". Annals of Oncology. 28 (suppl_12): xii3–xii10. doi:10.1093/annonc/mdx544. PMID 29092006.
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