Skip to main content
SpringerLink
Log in

T-Cell Epitope Discovery for Therapeutic Cancer Vaccines

  • Protocol
  • First Online:
Vaccine Design

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1403))

Abstract

The success of recent immune checkpoint blockade trials in solid tumors has demonstrated the tremendous potential of immune-mediated treatment strategies for cancer therapy. These immune therapies activate preexisting cytotoxic CD8+ T cells (CTL) to selectively target and eradicate malignant cells. In vitro models suggest that these therapies may be more effective in combination with priming of CTL using cancer vaccines. CTL-mediated tumor targeting is achieved by its recognition of tumor antigenic epitopes presented on human leukocyte antigen (HLA) class I molecules by tumor cells. Discovering CTL-antigenic epitopes is therefore central to the design of therapeutic T-cell vaccines and immune monitoring of these complex immunotherapies. However, selecting and monitoring T-cell epitopes remains difficult due to the extensive polymorphism of HLA alleles and the presence of confounding non-immunogenic self-peptides. To overcome these challenges, this chapter presents methodologies for the design of CTL-targeted vaccines using selection of target HLA alleles, novel integrated computational strategies to predict HLA-class I CTL epitopes, and epitope validation methods using short-term ex vivo T-cell stimulation. This strategy results in the improved efficiency for selecting antigenic epitopes for CTL-mediated vaccines and for immune monitoring of tumor antigens.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kim H-J, Cantor H (2014) The path to reactivation of antitumor immunity and checkpoint immunotherapy. Cancer Immunol Res 2:926–936

    Article  CAS  PubMed  Google Scholar 

  2. Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480:480–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Penny ME, Aranda C, Vardas E, Moi H, Jessen H, Hillman R, Chang Y, Ferris D, Rouleau D, Bryan J, Ph D, Marshall JB, Vuocolo S, Barr E, Radley D, Haupt RM, Guris D (2011) Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 364:401–411

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chang M-H, Shen C-J, Lai M-S, Hsu H-M, Tzee-Chung W, Kong M-S, Liang D-C, Shau W-Y, Chen D-S (1997) Universal Hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma. N Engl J Med 336:1855–1859

    Article  CAS  PubMed  Google Scholar 

  5. Center for Disease Control and Prevention (2005) A comprehensive immunization strategy to eliminate transmission of Hepatitis B virus infection in the United States recommendations of the advisory committee. CDC MMWR Rep 54:1–32

    Google Scholar 

  6. Trimble CL, Frazer IH (2009) Development of therapeutic HPV vaccines. Lancet Oncol 10:975–980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–227

    Article  CAS  PubMed  Google Scholar 

  8. Blum JS, Wearsch PA, Cresswell P (2013) Pathways of antigen processing. Annu Rev Immunol 31:443–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hennecke J, Wiley DC (2001) T cell receptor-MHC interactions up close. Cell 104:1–4

    Article  CAS  PubMed  Google Scholar 

  10. Purcell AW, McCluskey J, Rossjohn J (2007) More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov 6:404–414

    Article  CAS  PubMed  Google Scholar 

  11. Riemer AB, Keskin DB, Zhang G, Handley M, Anderson KS, Brusic V, Reinhold B, Reinherz EL (2010) A conserved E7-derived cytotoxic T lymphocyte epitope expressed on human papillomavirus 16-transformed HLA-A2+ epithelial cancers. J Biol Chem 285:29608–29622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ernst B, Anderson KS (2015) Immunotherapy for the treatment of breast cancer. Curr Oncol Rep 17(2):5

    Article  PubMed  Google Scholar 

  13. Ma B, Xu Y, Hung C, Wu T (2010) HPV and therapeutic vaccines: where are we in 2010 ? Curr Cancer Ther Rev 6:81–103

    Article  CAS  Google Scholar 

  14. Rajasagi M, Shukla SA, Fritsch EF, Keskin DB, DeLuca D, Carmona E, Zhang W, Sougnez C, Cibulskis K, Sidney J, Stevenson K, Ritz J, Neuberg D, Brusic V, Gabriel S, Lander ES, Getz G, Hacohen N, Wu CJ (2014) Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124:453–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, Allison JP (2008) Epitope landscape in breast and colorectal cancer. Cancer Res 68:889–892

    Article  CAS  PubMed  Google Scholar 

  16. Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, Franci C, Cheung TK, Fritsche J, Weinschenk T, Modrusan Z, Mellman I, Lill JR (2014) Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515:572–576

    Article  CAS  PubMed  Google Scholar 

  17. Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, Rommelfanger D, Ilett E, Pease L, Pandha H, Harrington K, Selby P, Melcher A, Vile R (2012) Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol 30:337–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rammensee H-G, Singh-Jasuja H (2013) HLA ligandome tumor antigen discovery for personalized vaccine approach. Expert Rev Vaccines 12:1211–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rizvi NA, Hellmann MD, Kvistborg P, Makarov V, Jonathan J, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Bruggeman C, Gasmi B, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128

    Article  CAS  PubMed  Google Scholar 

  21. Fortier M-H, Caron E, Hardy M-P, Voisin G, Lemieux S, Perreault C, Thibault P (2008) The MHC class I peptide repertoire is molded by the transcriptome. J Exp Med 205:595–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lund O, Nielsen M, Kesmir C, Petersen AG, Lundegaard C, Worning P, Sylvester-Hvid C, Lamberth K, Røder G, Justesen S, Buus S, Brunak S (2004) Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics 55:797–810

    Article  CAS  PubMed  Google Scholar 

  23. Sette A, Sidney J (1999) Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 50:201–212

    Article  CAS  PubMed  Google Scholar 

  24. Vonderheide RH, Anderson KS, Hahn WC, Butler MO, Schultze JL, Nadler LM (2001) Characterization of HLA-A3-restricted cytotoxic T lymphocytes reactive against the widely expressed tumor antigen telomerase. Clin Cancer Res 7:3343–3348

    CAS  PubMed  Google Scholar 

  25. Honeyman MC, Brusic V, Stone NL, Harrison LC (1998) Neural network-based prediction of candidate T-cell epitopes. Nat Biotechnol 16:966–969

    Article  CAS  PubMed  Google Scholar 

  26. Moutaftsi M, Peters B, Pasquetto V, Tscharke DC, Sidney J, Bui H-H, Grey H, Sette A (2006) A consensus epitope prediction approach identifies the breadth of murine T(CD8+)-cell responses to vaccinia virus. Nat Biotechnol 24:817–819

    Article  CAS  PubMed  Google Scholar 

  27. Tenzer S, Peters B, Bulik S, Schoor O, Lemmel C, Schatz MM, Kloetzel P-M, Rammensee H-G, Schild H, Holzhütter H-G (2005) Modeling the MHC class I pathway by combining predictions of proteasomal cleavage, TAP transport and MHC class I binding. Cell Mol Life Sci 62:1025–1037

    Article  CAS  PubMed  Google Scholar 

  28. Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S, Røder G, Peters B, Sette A, Lund O, Buus S (2007) NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS One 2:1–10

    Google Scholar 

  29. Calis JJA, Maybeno M, Greenbaum J, Weiskopf D, De Silva AD, Sette A, Keşmir C, Peters B (2013) Properties of MHC Class I presented peptides that enhance immunogenicity. PLoS Comput Biol 9:1–13

    Article  Google Scholar 

  30. Chowell D, Krishna S, Becker PD, Cocita C, Shu J, Tan X, Greenberg PD, Klavinskis LS, Blattman JN, Anderson KS (2015) TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes. Proc Natl Acad Sci 112:E1754–E1762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nielsen M, Lund O, Buus S, Lundegaard C (2010) MHC Class II epitope predictive algorithms. Immunology 130:319–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vonderheide RH, Schultze JL, Anderson KS, Maecker B et al (2001) Equivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing patients and healthy individuals. Cancer Res 61:8366–8370

    CAS  PubMed  Google Scholar 

  33. Hirano N, Butler MO, Xia Z, Berezovskaya A, Murray AP, Ansén S, Nadler LM (2006) Efficient presentation of naturally processed HLA class I peptides by artificial antigen-presenting cells for the generation of effective antitumor responses. Clin Cancer Res 12:2967–29675

    Article  CAS  PubMed  Google Scholar 

  34. Newell EW, Sigal N, Nair N, Kidd B, Greenberg HB, Davis MM (2013) Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. Nat Biotechnol 31:623–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Newell EW, Davis MM (2014) Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells. Nat Biotechnol 32:149–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lin HH, Ray S, Tongchusak S, Reinherz EL, Brusic V (2008) Evaluation of MHC class I peptide binding prediction servers: applications for vaccine research. BMC Immunol 9:1–13

    Article  Google Scholar 

  37. Rammensee H, Bachmann J, Emmerich NPN, Bachor OA, Stevanović S (2000) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 213–219

    Google Scholar 

  38. Kim Y, Sidney J, Pinilla C, Sette A, Peters B (2009) Derivation of an amino acid similarity matrix for peptide: MHC binding and its application as a Bayesian prior. BMC Bioinformatics 10:394

    Article  PubMed  PubMed Central  Google Scholar 

  39. Hida N, Maeda Y, Katagiri K, Takasu H, Harada M, Itoh K (2002) A simple culture protocol to detect peptide-specific cytotoxic T lymphocyte precursors in the circulation. Cancer Immunol Immunother 51:219–228

    Article  CAS  PubMed  Google Scholar 

  40. Parikh F, Duluc D, Imai N, Clark A, Misiukiewicz K et al (2014) Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. Cancer Res 74:7205–7216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH et al (2013) Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res 73:1733–1741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Binder DC, Engels B, Arina A, Yu P, Slauch JM et al (2013) Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer. Cancer Immunol Res 1:123–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pruitt KD, Brown GR, Hiatt SM, Thibaud-Nissen F et al (2014) RefSeq: an update on mammalian reference sequences. Nucleic Acids Res 42:756–763

    Article  Google Scholar 

  44. Consortium TU (2014) UniProt: a hub for protein information. Nucleic Acids Res 43:D204–D212

    Article  Google Scholar 

  45. Development Core Team R (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria

    Google Scholar 

Download references

Acknowledgements

We thank Diego Chowell for assistance with the normalization of prediction algorithms and epitope discovery strategy. This chapter describes work supported by institutional funds from Arizona State University to S.K. and K.S.A.

Author information

Authors and Affiliations

  1. Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA

    Sri Krishna & Karen S. Anderson M.D., Ph.D.

  2. School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287, USA

    Sri Krishna

Authors
  1. Sri Krishna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen S. Anderson M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen S. Anderson M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA

    Sunil Thomas

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Krishna, S., Anderson, K.S. (2016). T-Cell Epitope Discovery for Therapeutic Cancer Vaccines. In: Thomas, S. (eds) Vaccine Design. Methods in Molecular Biology, vol 1403. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3387-7_45

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3387-7_45

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3385-3

  • Online ISBN: 978-1-4939-3387-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation