Cancer Immunology, Immunotherapy

, Volume 64, Issue 1, pp 99–104 | Cite as

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

  • Zlatko Trajanoski
  • Cristina Maccalli
  • Daniele Mennonna
  • Giulia Casorati
  • Giorgio ParmianiEmail author
  • Paolo DellabonaEmail author
Focussed Research Review


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.


Tumor immunology Immunotherapy Tumor antigens Somatic mutations Oncogenomics NIBIT 2013 



Adoptive T cell therapy




Candidate cancer genes


Exome sequencing


Monoclonal antibody


Microsatellite instable


Microsatellite stable


RNA sequencing


Single nucleotide polymorphism


Tumor-associated antigens


Tell receptor


The Cancer Genome Atlas


CD4+CD25+T regulatory cells





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.


  1. 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 14:135–146CrossRefGoogle Scholar
  2. 2.
    Gilboa E (1999) The makings of a tumor rejection antigen. Immunity 11:263–270PubMedCrossRefGoogle Scholar
  3. 3.
    Novellino L, Castelli C, Parmiani G (2005) A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 54:187–207PubMedCrossRefGoogle Scholar
  4. 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 94:805–818PubMedCrossRefGoogle Scholar
  5. 5.
    Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909–915PubMedCentralPubMedCrossRefGoogle Scholar
  6. 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. 115:739–746PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422PubMedCrossRefGoogle Scholar
  8. 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. 5:463–476PubMedCrossRefGoogle Scholar
  9. 9.
    Savage PA, Leventhal DS, Malchow S (2014) Shaping the repertoire of tumor-infiltrating effector and regulatory T cells. Immunol Rev 259:245–258PubMedCrossRefGoogle Scholar
  10. 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 63:2535–2545PubMedGoogle Scholar
  11. 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 19:465–472PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778PubMedGoogle Scholar
  13. 13.
    Klein G, Sjogren HO, Klein E, Hellstrom KE (1960) Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 20:1561–1572PubMedGoogle Scholar
  14. 14.
    Mumberg D, Wick M, Schreiber H (1996) Unique tumor antigens redefined as mutant tumor-specific antigens. Semin Immunol 8:289–293PubMedCrossRefGoogle Scholar
  15. 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 58:293–303PubMedCrossRefGoogle Scholar
  16. 16.
    Foley EJ (1953) Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res 13:835–837PubMedGoogle Scholar
  17. 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 20:395–425PubMedCrossRefGoogle Scholar
  18. 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 62:967–974PubMedCentralPubMedCrossRefGoogle Scholar
  19. 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 61:222–227PubMedGoogle Scholar
  20. 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. 171:3467–3474PubMedCrossRefGoogle Scholar
  21. 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 9:3235–3245PubMedGoogle Scholar
  22. 22.
    Parmiani G, Testori A, Maio M et al (2004) Heat shock proteins and their use as anticancer vaccines. Clin Cancer Res 10:8142–8146PubMedCrossRefGoogle Scholar
  23. 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 269:1281–1284PubMedCrossRefGoogle Scholar
  24. 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 92:7976–7980PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Lawrence MS, Stojanov P, Polak P et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Lawrence MS, Stojanov P, Mermel CH et al (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:495–501PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Margulies M, Egholm M, Altman WE et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–380PubMedCentralPubMedGoogle Scholar
  30. 30.
    Thomas RK, Baker AC, Debiasi RM et al (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347–351PubMedCrossRefGoogle Scholar
  31. 31.
    Garraway LA, Lander ES (2013) Lessons from the cancer genome. Cell 153:17–37PubMedCrossRefGoogle Scholar
  32. 32.
    Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337CrossRefGoogle Scholar
  33. 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 184:441–447PubMedCrossRefGoogle Scholar
  34. 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 102:16013–16018PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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. 156:208–217PubMedGoogle Scholar
  36. 36.
    Parmiani G, De Filippo A, Novellino L, Castelli C (2007) Unique human tumor antigens: immunobiology and use in clinical trials. J Immunol. 178:1975–1979PubMedCrossRefGoogle Scholar
  37. 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 19:747–752PubMedCentralPubMedCrossRefGoogle Scholar
  38. 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 31:439–442CrossRefGoogle Scholar
  39. 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 344:641–645PubMedCrossRefGoogle Scholar
  40. 40.
    Matsushita H, Vesely MD, Koboldt DC et al (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404PubMedCrossRefGoogle Scholar
  41. 41.
    Thornton AM, Shevach EM (2000) Suppressor effector function of CD4 + CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 164:183–190PubMedCrossRefGoogle Scholar
  42. 42.
    von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338–344CrossRefGoogle Scholar
  43. 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 66:7301–7309PubMedCrossRefGoogle Scholar
  44. 44.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nature Rev Cancer. 12:252–264CrossRefGoogle Scholar
  45. 45.
    Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCentralPubMedCrossRefGoogle Scholar
  46. 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 366:2443–2454PubMedCentralPubMedCrossRefGoogle Scholar
  47. 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 12:852–855PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang Q, Wang P, Kim Y et al (2008) Immune epitope database analysis resource (IEDB-AR). Nucleic Acids Res 36:W513–W518PubMedCentralPubMedCrossRefGoogle Scholar
  49. 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–W512PubMedCentralPubMedCrossRefGoogle Scholar
  50. 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:e1000107PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Castle JC, Kreiter S, Diekmann J et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091PubMedCrossRefGoogle Scholar
  52. 52.
    Rajasagi M, Shukla SA, Fritsch EF et al (2014) Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124:453–462PubMedCrossRefGoogle Scholar
  53. 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 68:889–892PubMedCrossRefGoogle Scholar
  54. 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. 2:522–529PubMedCrossRefGoogle Scholar
  55. 55.
    Bindea G, Mlecnik B, Tosolini M et al (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39:782–795PubMedCrossRefGoogle Scholar
  56. 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 313:1960–1964PubMedCrossRefGoogle Scholar
  57. 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 61:1885–1903PubMedCentralPubMedCrossRefGoogle Scholar
  58. 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. 192:523–532PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Zlatko Trajanoski
    • 1
  • Cristina Maccalli
    • 2
  • Daniele Mennonna
    • 3
  • Giulia Casorati
    • 3
  • Giorgio Parmiani
    • 4
    Email author
  • Paolo Dellabona
    • 3
    Email author
  1. 1.Biocenter, Division for BioinformaticsInnsbruck Medical UniversityInnsbruckAustria
  2. 2.NIBIT Laboratory, Division of Medical Oncology and ImmunotherapyAzienda Ospedaliera UniversitariaSienaItaly
  3. 3.Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious DiseasesSan Raffaele Scientific InstituteMilanItaly
  4. 4.Solid Tumor Immuno-Biotherapy Unit, Division of Molecular OncologySan Raffaele Scientific InstituteMilanItaly

Personalised recommendations