Neoepitope Explained

Neoepitopes are a class of major histocompatibility complex (MHC) bounded peptides.[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] Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA) correlates with the number of neoepitopes, and have been suggested to correlate with patient survival post immunotherapy, although the findings about the neoantigen/immunogenicity association are disputed.[6] [7] [8] [9]

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.[10]

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.[11]

As target for immunotherapy

Cancer is a patient-specific disease, and no two tumors are alike. Thus, the immunogenicity of each tumor is unique.[12] A novel strategy against cancer is epitope selection for mutanome-directed individualized cancer immunotherapy.

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.[13] 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.[14]

Cancer vaccines

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.[15] 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.[16] [17] [18] [19]

Notes and References

  1. Leclerc M, Mezquita L, Guillebot De Nerville G, Tihy I, Malenica I, Chouaib S, Mami-Chouaib F . Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing . Frontiers in Immunology . 10 . 1505 . 2019 . 31333652 . 6616108 . 10.3389/fimmu.2019.01505 . free .
  2. Vormehr M, Diken M, Boegel S, Kreiter S, Türeci Ö, Sahin U . Mutanome directed cancer immunotherapy . Current Opinion in Immunology . 39 . 14–22 . April 2016 . 26716729 . 10.1016/j.coi.2015.12.001 .
  3. Katsnelson A . Mutations as munitions: Neoantigen vaccines get a closer look as cancer treatment . Nature Medicine . 22 . 2 . 122–4 . February 2016 . 26845402 . 10.1038/nm0216-122 . 26454626 .
  4. Vormehr M, Türeci Ö, Sahin U . Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines . Annual Review of Medicine . 70 . 395–407 . January 2019 . 30691374 . 10.1146/annurev-med-042617-101816 . 59341051 .
  5. Heemskerk B, Kvistborg P, Schumacher TN . The cancer antigenome . The EMBO Journal . 32 . 2 . 194–203 . January 2013 . 23258224 . 3553384 . 10.1038/emboj.2012.333 .
  6. Gurjao C, Tsukrov D, Imakaev M, Luquette LJ, Mirny LA . 2020-09-04. Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy . bioRxiv. en. 2020.09.03.260265. 10.1101/2020.09.03.260265. 221565320.
  7. Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Arnon L, Zimmer L, Gutzmer R, Satzger I, Loquai C, Grabbe S, Vokes N, Margolis CA, Conway J, He MX, Elmarakeby H, Dietlein F, Miao D, Tracy A, Gogas H, Goldinger SM, Utikal J, Blank CU, Rauschenberg R, von Bubnoff D, Krackhardt A, Weide B, Haferkamp S, Kiecker F, Izar B, Garraway L, Regev A, Flaherty K, Paschen A, Van Allen EM, Schadendorf D . 6 . Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma . Nature Medicine . 25 . 12 . 1916–1927 . December 2019 . 31792460 . 6898788 . 10.1038/s41591-019-0654-5 .
  8. Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, Mu XJ, Ching KA, Uemura M, Pal SK, Alekseev B, Gravis G, Campbell MT, Penkov K, Lee JL, Hariharan S, Wang X, Zhang W, Wang J, Chudnovsky A, di Pietro A, Donahue AC, Choueiri TK . 6 . Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial . Nature Medicine . 26 . 11 . 1733–1741 . November 2020 . 32895571 . 10.1038/s41591-020-1044-8 . 8493486 . free .
  9. Wood MA, Weeder BR, David JK, Nellore A, Thompson RF . Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival . Genome Medicine . 12 . 1 . 33 . March 2020 . 32228719 . 7106909 . 10.1186/s13073-020-00729-2 . free .
  10. James EA, Pietropaolo M, Mamula MJ . Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance . Diabetes . 67 . 6 . 1035–1042 . June 2018 . 29784651 . 5961411 . 10.2337/dbi17-0030 . free .
  11. Wilson EA, Anderson KS . Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy . Expert Review of Proteomics . 15 . 12 . 1065–1077 . December 2018 . 30408427 . 10.1080/14789450.2018.1545578 . 53242832 .
  12. Brennick CA, George MM, Corwin WL, Srivastava PK, Ebrahimi-Nik H . Neoepitopes as cancer immunotherapy targets: key challenges and opportunities . Immunotherapy . 9 . 4 . 361–371 . March 2017 . 28303769 . 10.2217/imt-2016-0146 . free .
  13. Feng YY, Griffith OL, Griffith M . Clinical implications of neoepitope landscapes for adult and pediatric cancers . Genome Medicine . 9 . 1 . 77 . August 2017 . 28854952 . 5577778 . 10.1186/s13073-017-0470-9 . free .
  14. Saini SK, Rekers N, Hadrup SR . Novel tools to assist neoepitope targeting in personalized cancer immunotherapy . Annals of Oncology . 28 . suppl_12 . xii3–xii10 . December 2017 . 29092006 . 10.1093/annonc/mdx544 . free .
  15. Türeci Ö, Vormehr M, Diken M, Kreiter S, Huber C, Sahin U . Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines . Clinical Cancer Research . 22 . 8 . 1885–96 . April 2016 . 27084742 . 10.1158/1078-0432.CCR-15-1509 . free .
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  17. Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ . 6 . An immunogenic personal neoantigen vaccine for patients with melanoma . Nature . 547 . 7662 . 217–221 . July 2017 . 28678778 . 5577644 . 10.1038/nature22991 . 2017Natur.547..217O .
  18. Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, Platten M, Tabatabai G, Dutoit V, van der Burg SH, Thor Straten P, Martínez-Ricarte F, Ponsati B, Okada H, Lassen U, Admon A, Ottensmeier CH, Ulges A, Kreiter S, von Deimling A, Skardelly M, Migliorini D, Kroep JR, Idorn M, Rodon J, Piró J, Poulsen HS, Shraibman B, McCann K, Mendrzyk R, Löwer M, Stieglbauer M, Britten CM, Capper D, Welters MJ, Sahuquillo J, Kiesel K, Derhovanessian E, Rusch E, Bunse L, Song C, Heesch S, Wagner C, Kemmer-Brück A, Ludwig J, Castle JC, Schoor O, Tadmor AD, Green E, Fritsche J, Meyer M, Pawlowski N, Dorner S, Hoffgaard F, Rössler B, Maurer D, Weinschenk T, Reinhardt C, Huber C, Rammensee HG, Singh-Jasuja H, Sahin U, Dietrich PY, Wick W . 6 . Actively personalized vaccination trial for newly diagnosed glioblastoma . Nature . 565 . 7738 . 240–245 . January 2019 . 30568303 . 10.1038/s41586-018-0810-y . 2019Natur.565..240H . 56480674 .
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