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
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    206 Chan
  2. Ronald P Dematteo
    588 Dematteo
  3. Jedd D Wolchok
    607 Wolchok
  4. Taha Merghoub
    169 Merghoub
  5. Mithat Gonen
    687 Gonen
  6. Nadeem Riaz
    205 Riaz
  7. Olca Basturk
    202 Basturk
  8. Peter Allen
    427 Allen
  9. Umeshkumar Kapaldev Bhanot
    36 Bhanot
  10. Olivera Grbovic
    15 Grbovic
  11. Vladimir Makarov
    30 Makarov
  12. Steven Leach
    23 Leach
  13. Gokce Askan
    39 Askan
  14. Marc   Attiyeh
    20 Attiyeh
  15. Jennifer Qi Zhang
    12 Zhang
  16. Benjamin Medina
    6 Medina
  17. Jennifer Loo
    8 Loo
  18. Nanyi Zhao
    4 Zhao
  19. Brian Thomas Herbst
    3 Herbst
  20. John Alec Gaite Moral
    3 Moral