Skip to main content

Advertisement

SpringerLink
Log in

Somatically mutated tumor antigens in the quest for a more efficacious patient-oriented immunotherapy of cancer

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Although cancer immunotherapy shows efficacy with adoptive T cell therapy (ACT) and antibody-based immune checkpoint blockade, efficacious therapeutic vaccination of cancer patients with tumor-associated antigens (TAAs) remains largely unmet. Current cancer vaccines utilize nonmutated shared TAAs that may have suboptimal immunogenicity. Experimental evidence underscores the strong immunogenicity of unique TAAs derived from somatically mutated cancer proteins, whose massive characterization has been precluded until recently by technical limitations. The development of cost-effective, high-throughput DNA sequencing approaches makes now possible the rapid identification of all the somatic mutations contained in a cancer cell genome. This method, combined with robust bioinformatics platforms for T cell epitope prediction and established reverse immunology approaches, provides us with an integrated strategy to identify patient-specific unique TAAs in a relatively short time, compatible with their potential use in the clinic. Hence, it is now for the first time possible to quantitatively define the patient’s unique tumor antigenome and exploit it for vaccination, possibly in combination with ACT and/or immune checkpoint blockade to further increase immunotherapy efficacy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ACT:

Adoptive T cell therapy

Ags:

Antigens

CAN-genes:

Candidate cancer genes

exome-Seq:

Exome sequencing

mAb:

Monoclonal antibody

MSI:

Microsatellite instable

MSS:

Microsatellite stable

RNA-Seq:

RNA sequencing

SNP-array:

Single nucleotide polymorphism

TAAs:

Tumor-associated antigens

TCR:

Tell receptor

TCGA:

The Cancer Genome Atlas

Tregs:

CD4+CD25+T regulatory cells

UV:

Ultraviolet

References

  1. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nature Rev Cancer 14:135–146

    Article  CAS  Google Scholar 

  2. Gilboa E (1999) The makings of a tumor rejection antigen. Immunity 11:263–270

    Article  CAS  PubMed  Google Scholar 

  3. Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 54:187–207

    Article  CAS  PubMed  Google Scholar 

  4. Parmiani G, Castelli C, Dalerba P, Mortarini R, Rivoltini L, Marincola FM, Anichini A (2002) Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst 94:805–818

    Article  CAS  PubMed  Google Scholar 

  5. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P (2005) Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest. 115:739–746

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422

    Article  CAS  PubMed  Google Scholar 

  8. Rivoltini L, Canese P, Huber V et al (2005) Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opin Biol Ther. 5:463–476

    Article  CAS  PubMed  Google Scholar 

  9. Savage PA, Leventhal DS, Malchow S (2014) Shaping the repertoire of tumor-infiltrating effector and regulatory T cells. Immunol Rev 259:245–258

    Article  CAS  PubMed  Google Scholar 

  10. Mortarini R, Piris A, Maurichi A et al (2003) Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. Cancer Res 63:2535–2545

    CAS  PubMed  Google Scholar 

  11. Hailemichael Y, Dai Z, Jaffarzad N et al (2013) Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med 19:465–472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778

    CAS  PubMed  Google Scholar 

  13. Klein G, Sjogren HO, Klein E, Hellstrom KE (1960) Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 20:1561–1572

    CAS  PubMed  Google Scholar 

  14. Mumberg D, Wick M, Schreiber H (1996) Unique tumor antigens redefined as mutant tumor-specific antigens. Semin Immunol 8:289–293

    Article  CAS  PubMed  Google Scholar 

  15. Lurquin C, Van Pel A, Mariame B, De Plaen E, Szikora JP, Janssens C, Reddehase MJ, Lejeune J, Boon T (1989) Structure of the gene of tum- transplantation antigen P91A: the mutated exon encodes a peptide recognized with Ld by cytolytic T cells. Cell 58:293–303

    Article  CAS  PubMed  Google Scholar 

  16. Foley EJ (1953) Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 13:835–837

    CAS  PubMed  Google Scholar 

  17. Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425

    Article  CAS  PubMed  Google Scholar 

  18. Srivastava PK, Duan F (2013) Harnessing the antigenic fingerprint of each individual cancer for immunotherapy of human cancer: genomics shows a new way and its challenges. Cancer Immunol Immunother 62:967–974

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Castelli C, Ciupitu AM, Rini F, Rivoltini L, Mazzocchi A, Kiessling R, Parmiani G (2001) Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells. Cancer Res 61:222–227

    CAS  PubMed  Google Scholar 

  20. Rivoltini L, Castelli C, Carrabba M et al (2003) Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells. J Immunol. 171:3467–3474

    Article  CAS  PubMed  Google Scholar 

  21. Mazzaferro V, Coppa J, Carrabba MG et al (2003) Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 9:3235–3245

    CAS  PubMed  Google Scholar 

  22. Parmiani G, Testori A, Maio M et al (2004) Heat shock proteins and their use as anticancer vaccines. Clin Cancer Res 10:8142–8146

    Article  CAS  PubMed  Google Scholar 

  23. Wolfel T, Hauer M, Schneider J et al (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:1281–1284

    Article  CAS  PubMed  Google Scholar 

  24. Coulie PG, Lehmann F, Lethe B, Herman J, Lurquin C, Andrawiss M, Boon T (1995) A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci USA 92:7976–7980

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Lawrence MS, Stojanov P, Polak P et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Lawrence MS, Stojanov P, Mermel CH et al (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:495–501

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Margulies M, Egholm M, Altman WE et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–380

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Thomas RK, Baker AC, Debiasi RM et al (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347–351

    Article  CAS  PubMed  Google Scholar 

  31. Garraway LA, Lander ES (2013) Lessons from the cancer genome. Cell 153:17–37

    Article  CAS  PubMed  Google Scholar 

  32. Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337

    Article  Google Scholar 

  33. Dudley ME, Roopenian DC (1996) Loss of a unique tumor antigen by cytotoxic T lymphocyte immunoselection from a 3-methylcholanthrene-induced mouse sarcoma reveals secondary unique and shared antigens. J Exp Med 184:441–447

    Article  CAS  PubMed  Google Scholar 

  34. Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, Wolfel C, Huber C, Wolfel T (2005) The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci USA 102:16013–16018

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Anichini A, Mortarini R, Maccalli C, Squarcina P, Fleischhauer K, Mascheroni L, Parmiani G (1996) Cytotoxic T cells directed to tumor antigens not expressed on normal melanocytes dominate HLA-A2.1-restricted immune repertoire to melanoma. J Immunol. 156:208–217

    CAS  PubMed  Google Scholar 

  36. Parmiani G, De Filippo A, Novellino L, Castelli C (2007) Unique human tumor antigens: immunobiology and use in clinical trials. J Immunol. 178:1975–1979

    Article  CAS  PubMed  Google Scholar 

  37. Robbins PF, Lu YC, El-Gamil M et al (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19:747–752

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. van Rooij N, van Buuren MM, Philips D et al (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31:439–442

    Article  Google Scholar 

  39. Tran E, Turcotte S, Gros A et al (2014) Cancer immunotherapy based on mutation-specific CD4+ T Cells in a patient with epithelial cancer. Science 344:641–645

    Article  CAS  PubMed  Google Scholar 

  40. Matsushita H, Vesely MD, Koboldt DC et al (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404

    Article  CAS  PubMed  Google Scholar 

  41. Thornton AM, Shevach EM (2000) Suppressor effector function of CD4 + CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 164:183–190

    Article  CAS  PubMed  Google Scholar 

  42. von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338–344

    Article  Google Scholar 

  43. Bui JD, Uppaluri R, Hsieh CS, Schreiber RD (2006) Comparative analysis of regulatory and effector T cells in progressively growing versus rejecting tumors of similar origins. Cancer Res 66:7301–7309

    Article  CAS  PubMed  Google Scholar 

  44. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nature Rev Cancer. 12:252–264

    Article  CAS  Google Scholar 

  45. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Thomas RK, Nickerson E, Simons JF et al (2006) Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing. Nat Med 12:852–855

    Article  CAS  PubMed  Google Scholar 

  48. Zhang Q, Wang P, Kim Y et al (2008) Immune epitope database analysis resource (IEDB-AR). Nucleic Acids Res 36:W513–W518

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund O, Nielsen M (2008) NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8-11. Nucleic Acids Res 36:W509–W512

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S, Buus S, Lund O (2008) Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLoS Comput Biol 4:e1000107

    Article  PubMed Central  PubMed  Google Scholar 

  51. Castle JC, Kreiter S, Diekmann J et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091

    Article  CAS  PubMed  Google Scholar 

  52. Rajasagi M, Shukla SA, Fritsch EF et al (2014) Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124:453–462

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Fritsch EF, Rajasagi M, Ott PA, Brusic V, Hacohen N, Wu CJ (2014) HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol Res. 2:522–529

    Article  CAS  PubMed  Google Scholar 

  55. Bindea G, Mlecnik B, Tosolini M et al (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39:782–795

    Article  CAS  PubMed  Google Scholar 

  56. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  CAS  PubMed  Google Scholar 

  57. Charoentong P, Angelova M, Efremova M, Gallasch R, Hackl H, Galon J, Trajanoski Z (2012) Bioinformatics for cancer immunology and immunotherapy. Cancer Immunol Immunother 61:1885–1903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Volonte A, Di Tomaso T, Spinelli M et al (2014) Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol. 192:523–532

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by Associazione Italiana per la Ricerca sul Cancro-AIRC to G. Casorati, G.Parmiani and P.Dellabona.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Biocenter, Division for Bioinformatics, Innsbruck Medical University, Innrain 80, 6020, Innsbruck, Austria

    Zlatko Trajanoski

  2. NIBIT Laboratory, Division of Medical Oncology and Immunotherapy, Azienda Ospedaliera Universitaria, Siena, Italy

    Cristina Maccalli

  3. Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina, 58, 20132, Milan, Italy

    Daniele Mennonna, Giulia Casorati & Paolo Dellabona

  4. Solid Tumor Immuno-Biotherapy Unit, Division of Molecular Oncology, San Raffaele Scientific Institute, Via Olgettina, 58, 20132, Milan, Italy

    Giorgio Parmiani

Authors
  1. Zlatko Trajanoski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Maccalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniele Mennonna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giulia Casorati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giorgio Parmiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paolo Dellabona
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Giorgio Parmiani or Paolo Dellabona.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Eleventh Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, held in Siena, Italy, 17th–19th October 2013. It is part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trajanoski, Z., Maccalli, C., Mennonna, D. et al. Somatically mutated tumor antigens in the quest for a more efficacious patient-oriented immunotherapy of cancer. Cancer Immunol Immunother 64, 99–104 (2015). https://doi.org/10.1007/s00262-014-1599-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1599-7

Keywords

Search

Navigation