Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer Journal Article


Authors: Balachandran, V. P.; Luksza, M.; Zhao, J. N.; Makarov, V.; Moral, J. A.; Remark, R.; Herbst, B.; Askan, G.; Bhanot, U.; Senbabaoglu, Y.; Wells, D. K.; Cary, C. I. O.; Grbovic-Huezo, O.; Attiyeh, M.; Medina, B.; Zhang, J.; Loo, J.; Saglimbeni, J.; Abu-Akeel, M.; Zappasodi, R.; Riaz, N.; Smoragiewicz, M.; Kelley, Z. L.; Basturk, O.; Australian Pancreatic Cancer Genome Initiative; Gönen, M.; Levine, A. J.; Allen, P. J.; Fearon, D. T.; Merad, M.; Gnjatic, S.; Iacobuzio-Donahue, C. A.; Wolchok, J. D.; DeMatteo, R. P.; Chan, T. A.; Greenbaum, B. D.; Merghoub, T.; Leach, S. D.
Article Title: Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer
Abstract: 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 survivors, 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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Keywords: immunohistochemistry; survival; adult; clinical article; controlled study; aged; unclassified drug; human cell; cd8+ t lymphocyte; protein analysis; gene expression; gene frequency; peptide; cancer survivor; antigen; biomarker; immunogenicity; epitope; pancreas adenocarcinoma; immunity; ca 125 antigen; tumor; model; t lymphocyte activation; disease treatment; biophysics; clone; t lymphocyte antigen; homology; cells and cell components; cancer; human; male; female; priority journal; article; whole exome sequencing; neoantigen
Journal Title: Nature
Volume: 551
Issue: 7681
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2017-11-23
Start Page: 512
End Page: 516
Language: English
DOI: 10.1038/nature24462
PROVIDER: scopus
PUBMED: 29132146
PMCID: PMC6145146
DOI/URL:
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    317 Chan
  2. Ronald P DeMatteo
    637 DeMatteo
  3. Jedd D Wolchok
    905 Wolchok
  4. Taha Merghoub
    364 Merghoub
  5. Mithat Gonen
    1029 Gonen
  6. Nadeem Riaz
    416 Riaz
  7. Olca Basturk
    352 Basturk
  8. Peter Allen
    501 Allen
  9. Umeshkumar Kapaldev Bhanot
    93 Bhanot
  10. Vladimir Makarov
    57 Makarov
  11. Steven Leach
    37 Leach
  12. Gokce Askan
    77 Askan
  13. Marc   Attiyeh
    30 Attiyeh
  14. Jennifer Qi Zhang
    27 Zhang
  15. Benjamin Medina
    16 Medina
  16. Jennifer Loo
    13 Loo
  17. Nanyi Zhao
    5 Zhao
  18. Brian Thomas Herbst
    5 Herbst
  19. John Alec Gaite Moral
    8 Moral