Skip to main content
SpringerLink
Log in

How T Cells Single Out Tumor Cells: “And That Has Made All the Difference…”

  • Chapter
  • First Online:
Cancer Immunotherapy Meets Oncology

  • 1910 Accesses

Abstract

It is now beyond doubt that different human tumor types can be recognized by the immune system and that cytotoxic T cells are a key player in this process. For long, efforts to understand and influence such tumor-specific T-cell reactivity have focused on the tumor-associated “self-antigens” that are also expressed in other tissues. However, many of the human tumors with high prevalence are characterized by a large number of mutations that alter open reading frames, thereby leading to the presentation of neo-antigens that are foreign to the immune system. Until recently, the fact that the large majority of mutations in human cancer are patient specific prevented efforts to exploit this repertoire of neo-antigens in cancer immunotherapy. However, recent work has drastically altered this situation.

Within this review we aim to provide a roadmap for the journey to be taken to develop patient-specific cancer immunotherapies that aim to target tumor-associated neo-antigens. First, we will introduce our current understanding of the recognition of tumor-associated neo-antigens in melanoma and the likelihood of neo-antigen recognition in other human tumor types. Second, we will discuss our knowledge on the potential of neo-antigens versus cancer germline antigens as targets in cancer immunotherapy. Finally, we will give some first directions on the road toward patient-specific immunotherapies that target the neo-antigen repertoire in human cancer.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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

  • Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinsk M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van’t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421. doi:10.1038/nature12477

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y, Ohayon D, Shalmon B, Markel G, Yerushalmi R, Apter S, Ben-Nun A, Ben-Ami E, Shimoni A, Nagler A, Schachter J (2013) Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res 19(17):4792–4800. doi:10.1158/1078-0432.CCR-13-0380

    Article  PubMed  CAS  Google Scholar 

  • Britten CM, Singh-Jasuja H, Flamion B, Hoos A, Huber C, Kallen KJ, Khleif SN, Kreiter S, Nielsen M, Rammensee HG, Sahin U, Hinz T, Kalinke U (2013) The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol 31(10):880–882. doi:10.1038/nbt.2708

    Article  PubMed  CAS  Google Scholar 

  • Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal SA, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Griffin CA, Burton J, Swerdlow H, Quail MA, Stratton MR, Iacobuzio-Donahue C, Futreal PA (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113. doi:10.1038/nature09460

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Castle JC, Kreiter S, Diekmann J, Lower M, van de Roemer N, de Graaf J, Selmi A, Diken M, Boegel S, Paret C, Koslowski M, Kuhn AN, Britten CM, Huber C, Tureci O, Sahin U (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72(5):1081–1091. doi:10.1158/0008-5472.CAN-11-3722

    Article  PubMed  CAS  Google Scholar 

  • Dudley ME, Gross CA, Langhan MM, Garcia MR, Sherry RM, Yang JC, Phan GQ, Kammula US, Hughes MS, Citrin DE, Restifo NP, Wunderlich JR, Prieto PA, Hong JJ, Langan RC, Zlott DA, Morton KE, White DE, Laurencot CM, Rosenberg SA (2010) CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res 16(24):6122–6131. doi:10.1158/1078-0432.CCR-10-1297

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Dudley ME, Gross CA, Somerville RP, Hong Y, Schaub NP, Rosati SF, White DE, Nathan D, Restifo NP, Steinberg SM, Wunderlich JR, Kammula US, Sherry RM, Yang JC, Phan GQ, Hughes MS, Laurencot CM, Rosenberg SA (2013) Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol 31(17):2152–2159. doi:10.1200/JCO.2012.46.6441

    Article  PubMed  CAS  Google Scholar 

  • Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. doi:10.1038/nrc3245

    Article  PubMed  CAS  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892. doi:10.1056/NEJMoa1113205

    Article  PubMed  CAS  Google Scholar 

  • Gilboa E (1999) The makings of a tumor rejection antigen. Immunity 11(3):263–270

    Article  PubMed  CAS  Google Scholar 

  • Gotter J, Brors B, Hergenhahn M, Kyewski B (2004) Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med 199(2):155–166. doi:10.1084/jem.20031677

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hadrup SR, Bakker AH, Shu CJ, Andersen RS, van Veluw J, Hombrink P, Castermans E, Thor Straten P, Blank C, Haanen JB, Heemskerk MH, Schumacher TN (2009) Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods 6(7):520–526. doi:10.1038/nmeth.1345

    Article  PubMed  CAS  Google Scholar 

  • Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. doi:10.1056/NEJMoa1305133

    Article  PubMed  CAS  Google Scholar 

  • Harndahl M, Rasmussen M, Roder G, Dalgaard Pedersen I, Sorensen M, Nielsen M, Buus S (2012) Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity. Eur J Immunol 42(6):1405–1416. doi:10.1002/eji.201141774

    Article  PubMed  CAS  Google Scholar 

  • Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. doi:10.1056/NEJMoa1003466

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hofmann O, Caballero OL, Stevenson BJ, Chen YT, Cohen T, Chua R, Maher CA, Panji S, Schaefer U, Kruger A, Lehvaslaiho M, Carninci P, Hayashizaki Y, Jongeneel CV, Simpson AJ, Old LJ, Hide W (2008) Genome-wide analysis of cancer/testis gene expression. Proc Natl Acad Sci U S A 105(51):20422–20427. doi:10.1073/pnas.0810777105

    Article  PubMed Central  PubMed  Google Scholar 

  • Kalialis LV, Drzewiecki KT, Klyver H (2009) Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res 19(5):275–282. doi:10.1097/CMR.0b013e32832eabd5

    Article  PubMed  Google Scholar 

  • Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339. doi:10.1038/nature12634

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kesmir C, Nussbaum AK, Schild H, Detours V, Brunak S (2002) Prediction of proteasome cleavage motifs by neural networks. Protein Eng 15(4):287–296

    Article  PubMed  CAS  Google Scholar 

  • Kvistborg P, van Buuren MM, Schumacher TN (2013) Human cancer regression antigens. Curr Opin Immunol 25(2):284–290. doi:10.1016/j.coi.2013.03.005

    Article  PubMed  CAS  Google Scholar 

  • 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 U S A 102(44):16013–16018. doi:10.1073/pnas.0500090102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, Litzky L, Bagg A, Carreno BM, Cimino PJ, Binder-Scholl GK, Smethurst DP, Gerry AB, Pumphrey NJ, Bennett AD, Brewer JE, Dukes J, Harper J, Tayton-Martin HK, Jakobsen BK, Hassan NJ, Kalos M, June CH (2013) Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122(6):863–871. doi:10.1182/blood-2013-03-490565

    Article  PubMed  CAS  Google Scholar 

  • Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482(7385):400–404. doi:10.1038/nature10755

    Article  PubMed  CAS  Google Scholar 

  • Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94. doi:10.1038/nature09807

    Article  PubMed  CAS  Google Scholar 

  • Nielsen M, Lundegaard C, Worning P, Lauemoller SL, Lamberth K, Buus S, Brunak S, Lund O (2003) Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci 12(5):1007–1017. doi:10.1110/ps.0239403

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ott PA, Hodi FS, Robert C (2013) CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 19(19):5300–5309. doi:10.1158/1078-0432.CCR-13-0143

    Article  PubMed  CAS  Google Scholar 

  • Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, Wu R, Lizee G, Mahoney S, Alvarado G, Glass M, Johnson VE, McMannis JD, Shpall E, Prieto V, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Patel S, Ross MI, Lee JE, Gershenwald JE, Lucci A, Royal R, Cormier JN, Davies MA, Mansaray R, Fulbright OJ, Toth C, Ramachandran R, Wardell S, Gonzalez A, Hwu P (2012) Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res 18(24):6758–6770. doi:10.1158/1078-0432.CCR-12-1177

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Robbins PF, El-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E, Rosenberg SA (1996) A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 183(3):1185–1192

    Article  PubMed  CAS  Google Scholar 

  • Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29(7):917–924. doi:10.1200/JCO.2010.32.2537

    Article  PubMed Central  PubMed  Google Scholar 

  • Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E, Samuels Y, Rosenberg SA (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. doi:10.1038/nm.3161

    Google Scholar 

  • Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21(2):233–240. doi:10.1016/j.coi.2009.03.002

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME (2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17(13):4550–4557. doi:10.1158/1078-0432.CCR-11-0116

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 331(6024):1553–1558. doi:10.1126/science.1204040

    Article  PubMed  CAS  Google Scholar 

  • Toebes M, Coccoris M, Bins A, Rodenko B, Gomez R, Nieuwkoop NJ, van de Kasteele W, Rimmelzwaan GF, Haanen JB, Ovaa H, Schumacher TN (2006) Design and use of conditional MHC class I ligands. Nat Med 12(2):246–251. doi:10.1038/nm1360

    Article  PubMed  CAS  Google Scholar 

  • Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, van Dijk LJ, Behjati S, Hilkmann H, El Atmioui D, Nieuwland M, Stratton MR, Kerkhoven RM, Kesmir C, Haanen JB, Kvistborg P, Schumacher TN (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. doi:10.1200/JCO.2012.47.7521

    PubMed Central  PubMed  Google Scholar 

  • Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18(8):1254–1261. doi:10.1038/nm.2883

    Article  PubMed  CAS  Google Scholar 

  • Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, O’Day SJ, Hoos A, Humphrey R, Berman DM, Lonberg N, Korman AJ (2013) Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 1291:1–13. doi:10.1111/nyas.12180

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Buschenfelde KH, Beach D (1995) A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269(5228):1281–1284

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank C. Linnemann for useful discussions.

This research was supported by KWF grant 2012-5463 and by a Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.

Author information

Authors and Affiliations

  1. Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Marit M. van Buuren, Pia Kvistborg & Ton N. M. Schumacher

Authors
  1. Marit M. van Buuren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pia Kvistborg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ton N. M. Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ton N. M. Schumacher .

Editor information

Editors and Affiliations

  1. Immunotherapy Development Center (IDC), TRON-Translational Oncology University Medical Center, Johannes Gutenberg University, Mainz, Germany

    Cedrik Michael Britten

  2. Department of Immunotherapy Development Center, TRON-Translational Oncology University Medical Center, Johannes Gutenberg-University, Mainz, Germany

    Sebastian Kreiter

  3. Department of Immunotherapy Development Center, TRON-Translational Oncology University Medical Center, Johannes Gutenberg University, Mainz, Germany

    Mustafa Diken

  4. Department of Immunology, University of Tübingen, Tübingen, Germany

    Hans-Georg Rammensee

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

van Buuren, M.M., Kvistborg, P., Schumacher, T.N.M. (2014). How T Cells Single Out Tumor Cells: “And That Has Made All the Difference…”. In: Britten, C., Kreiter, S., Diken, M., Rammensee, HG. (eds) Cancer Immunotherapy Meets Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-05104-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-05104-8_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-05103-1

  • Online ISBN: 978-3-319-05104-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation