Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

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We thank A. Rudensky, A. Snyder-Charan, C. Callan, Y. Elhanati, Z. Sethna, J. Leung, J. Ruan, C. Crabtree, P. Garcia, M. Singh, A. McNeil, D. Haviland, J. Melchor and J. Tsoi for discussions, technical and editorial assistance. This work was supported by National Institutes of Health (NIH) R01DK097087-01 Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant (S.D.L.), P30 CA008748-50S4 administrative supplement (S.D.L., V.P.B.), Suzanne Cohn Simon Pancreatic Cancer Research Fund (S.D.L.), National Cancer Institute K12CA184746-01A1 (V.P.B.), Damon Runyon Clinical Investigator Award (V.P.B.), Stand Up to Cancer, Lustgarden Foundation, and the National Science Foundation (J.D.W., B.D.G.), the V Foundation (V.P.B., J.A.M., J.D.W., B.D.G.), the Phil A. Sharp Innovation Award (B.D.G., J.D.W.), Swim Across America, and the Ludwig Institute for Cancer Research (J.D.W., T.M.), and the Parker Institute for Cancer Immunotherapy (D.K.W., C.I.O.C., J.D.W., T.M.). Services by the Integrated Genomics Core were funded by the National Cancer Institute Cancer Center Support Grant (P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

Author information

Author notes

    • Taha Merghoub
    •  & Steven D. Leach

    These authors jointly supervised this work.


  1. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Vinod P. Balachandran
    • , Julia N. Zhao
    • , John Alec Moral
    • , Marc Attiyeh
    • , Benjamin Medina
    • , Jennifer Zhang
    • , Jennifer Loo
    • , Peter J. Allen
    • , Ronald P. DeMatteo
    •  & Steven D. Leach
  2. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Vinod P. Balachandran
    • , Julia N. Zhao
    • , John Alec Moral
    • , Brian Herbst
    • , Gokce Askan
    • , Olivera Grbovic-Huezo
    • , Marc Attiyeh
    • , Joseph Saglimbeni
    • , Peter J. Allen
    • , Christine A. Iacobuzio-Donahue
    • , Ronald P. DeMatteo
    •  & Steven D. Leach
  3. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Vinod P. Balachandran
    • , Julia N. Zhao
    • , John Alec Moral
    • , Jedd D. Wolchok
    • , Timothy A. Chan
    •  & Taha Merghoub
  4. The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA

    • Marta Łuksza
    •  & Arnold J. Levine
  5. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Vladimir Makarov
    • , Christine A. Iacobuzio-Donahue
    • , Timothy A. Chan
    •  & Steven D. Leach
  6. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Vladimir Makarov
    • , Nadeem Riaz
    •  & Timothy A. Chan
  7. Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    • Romain Remark
    • , Miriam Merad
    •  & Sacha Gnjatic
  8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Gokce Askan
    • , Umesh Bhanot
    • , Olca Basturk
    •  & Christine A. Iacobuzio-Donahue
  9. Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA

    • Yasin Senbabaoglu
    • , Mohsen Abu-Akeel
    • , Roberta Zappasodi
    • , Jedd D. Wolchok
    •  & Taha Merghoub
  10. Parker Institute for Cancer Immunotherapy, San Francisco, California, USA

    • Daniel K. Wells
    •  & Charles Ian Ormsby Cary
  11. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Nadeem Riaz
    •  & Timothy A. Chan
  12. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK

    • Martin Smoragiewicz
  13. Cold Spring Harbor Laboratory, New York, New York, USA

    • Z. Larkin Kelley
    •  & Douglas T. Fearon
  14. Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA

    • Z. Larkin Kelley
    •  & Douglas T. Fearon
  15. Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Mithat Gönen
  16. Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Jedd D. Wolchok
  17. Weill Cornell Medical College, Cornell University, New York, New York, USA

    • Jedd D. Wolchok
  18. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    • Jedd D. Wolchok
    •  & Taha Merghoub
  19. Tisch Cancer Institute, Departments of Medicine, Hematology and Medical Oncology, Oncological Sciences, and Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    • Benjamin D. Greenbaum
  20. Dartmouth Norris Cotton Cancer Center, Lebanon, New Hampshire, USA

    • Steven D. Leach
  21. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia

    • Amber L. Johns
    • , R. Scott Mead
    • , Anthony J. Gill
    • , David K. Chang
    • , Skye H. McKay
    • , Lorraine A. Chantrill
    • , Venessa T. Chin
    • , Angela Chou
    • , Jeremy L. Humphris
    • , Marina Pajic
    • , Angela Steinmann
    • , Mehreen Arshi
    • , Ali Drury
    • , Danielle Froio
    • , Ashleigh Morgan
    • , Paul Timpson
    • , David Hermann
    • , Claire Vennin
    • , Sean Warren
    • , Mark Pinese
    • , Jianmin Wu
    •  & Andreia V. Pinho
  22. Prince of Wales Hospital, Barker Street, Randwick, New South Wales 2031, Australia

    • R. Scott Mead
    • , Katherine Tucker
    •  & Lesley Andrews
  23. Royal North Shore Hospital, Westbourne Street, St Leonards, New South Wales 2065, Australia

    • Anthony J. Gill
    • , Jaswinder S. Samra
    • , Jennifer Arena
    • , Nick Pavlakis
    • , Hilda A. High
    •  & Anubhav Mittal
  24. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK

    • David K. Chang
    • , Andrew V. Biankin
    • , Peter Bailey
    • , Sancha Martin
    • , Elizabeth A. Musgrove
    • , Marc D. Jones
    • , Craig Nourse
    •  & Nigel B. Jamieson
  25. St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, New South Wales, 2010 Australia

    • Lorraine A. Chantrill
    • , Angela Chou
    • , Alina Stoita
    • , David Williams
    •  & Allan Spigelman
  26. QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia

    • Nicola Waddell
    • , John V. Pearson
    • , Ann-Marie Patch
    • , Katia Nones
    • , Felicity Newell
    • , Pamela Mukhopadhyay
    • , Venkateswar Addala
    • , Stephen Kazakoff
    • , Oliver Holmes
    • , Conrad Leonard
    • , Scott Wood
    •  & Christina Xu
  27. University of Melbourne, Centre for Cancer Research, Victorian Comprehensive Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia

    • Sean M. Grimmond
    •  & Oliver Hofmann
  28. Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland 4072, Australia

    • Peter J. Wilson
    • , Angelika Christ
    •  & Tim Bruxner
  29. Bankstown Hospital, Eldridge Road, Bankstown, New South Wales 2200, Australia

    • Ray Asghari
    • , Neil D. Merrett
    • , Darren Pavey
    •  & Amitabha Das
  30. Liverpool Hospital, Elizabeth Street, Liverpool, New South Wales 2170, Australia

    • Annabel Goodwin
    • , Peter H. Cosman
    • , Kasim Ismail
    •  & Chelsie O’Connor
  31. Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia

    • Annabel Goodwin
    • , Caroline L. Cooper
    • , Peter Grimison
    • , James G. Kench
    •  & Charbel Sandroussi
  32. Westmead Hospital, Hawkesbury and Darcy Roads, Westmead, New South Wales 2145, Australia

    • Vincent W. Lam
    • , Duncan McLeod
    • , Adnan M. Nagrial
    • , Judy Kirk
    •  & Virginia James
  33. Fremantle Hospital, Alma Street, Fremantle, Western Australia 6959, Australia

    • Michael Texler
    • , Cindy Forest
    • , Krishna P. Epari
    • , Mo Ballal
    • , David R. Fletcher
    •  & Sanjay Mukhedkar
  34. St John of God Healthcare, 12 Salvado Road, Subiaco, Western Australia 6008, Australia

    • Nikolajs Zeps
    • , Maria Beilin
    •  & Kynan Feeney
  35. Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia

    • Nan Q. Nguyen
    • , Andrew R. Ruszkiewicz
    •  & Chris Worthley
  36. Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia 5042, Australia

    • John Chen
    • , Mark E. Brooke-Smith
    •  & Virginia Papangelis
  37. Envoi Pathology, 1/49 Butterfield Street, Herston, Queensland 4006, Australia

    • Andrew D. Clouston
    •  & Patrick Martin
  38. Princess Alexandria Hospital, Cornwall Street & Ipswich Road, Woolloongabba, Queensland 4102, Australia

    • Andrew P. Barbour
    • , Thomas J. O’Rourke
    • , Jonathan W. Fawcett
    • , Kellee Slater
    • , Michael Hatzifotis
    •  & Peter Hodgkinson
  39. Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia

    • Mehrdad Nikfarjam
  40. Johns Hopkins Medical Institute, 600 North Wolfe Street, Baltimore, Maryland 21287, USA

    • James R. Eshleman
    • , Ralph H. Hruban
    • , Christopher L. Wolfgang
    •  & Mary Hodgin
  41. ARC-NET Center for Applied Research on Cancer, University of Verona, Via dell’Artigliere, 19 37129 Verona, Province of Verona, Italy

    • Aldo Scarpa
    • , Rita T. Lawlor
    • , Stefania Beghelli
    • , Vincenzo Corbo
    • , Maria Scardoni
    •  & Claudio Bassi


  1. Australian Pancreatic Cancer Genome Initiative

    Garvan Institute of Medical Research

    Prince of Wales Hospital

    Royal North Shore Hospital

    University of Glasgow

    St Vincent’s Hospital

    QIMR Berghofer Medical Research Institute

    University of Melbourne, Centre for Cancer Research

    University of Queensland, Institute for Molecular Bioscience

    Bankstown Hospital

    Liverpool Hospital

    Royal Prince Alfred Hospital, Chris O’Brien Lifehouse

    Westmead Hospital

    Fremantle Hospital

    St John of God Healthcare

    Royal Adelaide Hospital

    Flinders Medical Centre

    Envoi Pathology

    Princess Alexandria Hospital

    Austin Hospital

    Johns Hopkins Medical Institutes

    ARC-Net Centre for Applied Research on Cancer


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V.P.B., M.Ł., P.J.A., D.T.F., J.D.W., R.P.D., B.D.G., T.A.C., T.M. and S.D.L. conceived the study and V.P.B., J.D.W., T.A.C., B.D.G., T.M. and S.D.L. designed all experiments. V.P.B., M.Ł., J.N.Z., V.M., J.A.M., R.R., B.H., G.A., U.B., Y.S., D.K.W., C.I.O.C., O.G.-H., M.A., B.M., J.Z., J.L., J.S., M.A.-A., R.Z., N.R., M.S., Z.L.K., O.B., A.J.L., P.J.A., D.T.F., M.M., S.G., C.A.I.-D. and members of the Australian Pancreatic Cancer Genome Initiative acquired and analysed data. G.A., U.B. and O.B. performed the histopathological analyses. M.A. and C.A.I.D. performed tissue acquisition, and mutational identification for rapid autopsy tissues. V.M., N.R., T.A.C., D.K.W. and C.I.O.C. performed the neoantigen identification. M.Ł. and B.D.G. constructed the neoantigen fitness models. V.P.B., J.N.Z., M.A.-A. and J.A.M. performed the in vitro T-cell assays. O.G.-H. performed the transfections, immunocytochemistry, and western blots. M.G. provided statistical oversight. V.P.B., M.Ł., J.N.Z., D.T.F., J.D.W., R.P.D., B.D.G., T.A.C., T.M. and S.D.L. interpreted the data. V.P.B., M.Ł., J.D.W., B.D.G., T.M. and S.D.L. drafted the manuscript.

Competing interests

V.P.B., V.M., N.R., J.D.W. and T.A.C. have received research funding from Bristol-Myers Squibb. N.R. has received honoraria from MedImmune. D.T.F. is a co-founder of Myosotis LLC. S.G. has received research support from Immune Design, Janssen R&D, and Agenus, and serves on advisory boards for Third Rock, Ventures/Neon Therapeutics, B4CC, and Oncomed Pharmaceuticals. M.M., S.G. and R.R. are inventors of a patent regarding ‘Tissue profiling using multiplexed immunohistochemical consecutive staining’ (patent number pending). T.A.C. is a co-founder of Gritstone Oncology and is also an advisor for Genocea, Cancer Genetics, and Illumina.

Corresponding author

Correspondence to Vinod P. Balachandran.

Reviewer Information Nature thanks E. Verdegaal, R. Vonderheide and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This file contains a comprehensive list of all neopeptide sequences and HLA alleles with predicted neopeptide binding in the MSKCC cohort.

  2. 2.

    Supplementary Table 2

    This file contains a comprehensive list of all human infectious derived, class-I restricted peptide sequences with positive immune assays derived from the Immune Epitope Database used in this study.

  3. 3.

    Supplementary Table 3

    This file contains a comprehensive list of all peptide sequences, respective HLA alleles with predicted binding, crossreacting microbial sequences, and microbial species (where applicable) used in this study.

  4. 4.

    Supplementary Table 4

    This file contains a comprehensive list of all human non-infectious (allergy/autoimmune) derived, class-I restricted peptide sequences with positive immune assays derived from the Immune Epitope Database used in this study.

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  1. 1.

    Supplementary Data 1

    This folder contains the source code for the neoantigen quality assessment performed in this manuscript. A text file of Supplementary Table 1 is included to enable code execution.

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