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

Vinod P. Balachandran, Marta Luksza, Julia N. Zhao, Vladimir Makarov, John Alec Moral, Romain Remark, Brian Herbst, Gokce Askan, Umesh Bhanot, Yasin Senbabaoglu, Daniel K. Wells, Charles Ian Ormsby Cary, Olivera Grbovic-Huezo, Marc Attiyeh, Benjamin Medina, Jennifer Zhang, Jennifer Loo, Joseph Saglimbeni, Mohsen Abu-Akeel, Roberta Zappasodi & 124 others Nadeem Riaz, Martin Smoragiewicz, Z. Larkin Kelley, Olca Basturk, Australian Pancreatic Cancer Genome Initiative, Mithat Goenen, Arnold J. Levine, Peter J. Allen, Douglas T. Fearon, Miriam Merad, Sacha Gnjatic, Christine A. Iacobuzio-Donahue, Jedd D. Wolchok, Ronald P. DeMatteo, Timothy A. Chan, Benjamin D. Greenbaum, Taha Merghoub, Steven D. Leach, Amber L. Johns, R. Scott Mead, Anthony J. Gill, David K. Chang, Skye H. McKay, Lorraine A. Chantrill, Venessa T. Chin, Chou Angela, Jeremy L. Humphris, Marina Pajic, Angela M. Steinmann, Mehreen Arshi, Ali Drury, Danielle Froio, Ashleigh Morgan, Paul Timpson, Claire Vennin, Sean Warren, Mark Pinese, Jianmin Wu, Andreia V. Pinho, Katherine Tucker, Lesley Andrews, Jaswinder S. Samra, Jennifer Arena, Nick Pavlakis, Hilda A. High, Anubhav Mittal, Andrew V. Biankin, Peter Bailey, Sancha Martin, Elizabeth A. Musgrove, Marc D. Jones, Craig Nourse, Nigel B. Jamieson, Alina Stoita, David Williams, Allan Spigellman, 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, Sean M. Grimmond, Oliver Hofmann, Peter J. Wilson, Angelika Christ, Tim Bruxner, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Annabel Goodwin, Peter H. Cosman, Kasim Ismail, Chelsie O'Connor, Caroline L. Cooper, Peter Grimison, James G. Kench, Charbel Sandroussi, Vincent W. Lam, Duncan McLeod, Adnan M. Nagrial, Judy Kirk, Virginia James, Michael Texler, Cindy Forrest, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Andrew D. Clouston, Patrick Martin, Andrew Barbour, Thomas J. O'Rourke, Jonathan W. Fawcett, Kellee Slater, Michael Hatzifotis, Peter Hodgkinson, Mehrdad Nikfarjam, James R. Eshleman, Ralph H. Hruban, Christopher L. Wolfgang, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi

Research output: Contribution to journalArticleResearchpeer-review

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 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.

LanguageEnglish
Pages512-516
Number of pages5
JournalNature
Volume551
Issue number7681
DOIs
Publication statusPublished - 23 Nov 2017
Externally publishedYes

Keywords

  • HUMAN-MELANOMA
  • PD-1 BLOCKADE
  • MUC16
  • CELLS
  • DYNAMICS
  • ANTIGEN
  • TUMORS
  • MICE

Cite this

Balachandran, V. P., Luksza, M., Zhao, J. N., Makarov, V., Moral, J. A., Remark, R., ... Bassi, C. (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 551(7681), 512-516. https://doi.org/10.1038/nature24462
Balachandran, Vinod P. ; Luksza, Marta ; Zhao, Julia N. ; Makarov, Vladimir ; Moral, John Alec ; Remark, Romain ; Herbst, Brian ; Askan, Gokce ; Bhanot, Umesh ; Senbabaoglu, Yasin ; Wells, Daniel K. ; Cary, Charles Ian Ormsby ; Grbovic-Huezo, Olivera ; Attiyeh, Marc ; Medina, Benjamin ; Zhang, Jennifer ; Loo, Jennifer ; Saglimbeni, Joseph ; Abu-Akeel, Mohsen ; Zappasodi, Roberta ; Riaz, Nadeem ; Smoragiewicz, Martin ; Kelley, Z. Larkin ; Basturk, Olca ; Australian Pancreatic Cancer Genome Initiative ; Goenen, Mithat ; Levine, Arnold J. ; Allen, Peter J. ; Fearon, Douglas T. ; Merad, Miriam ; Gnjatic, Sacha ; Iacobuzio-Donahue, Christine A. ; Wolchok, Jedd D. ; DeMatteo, Ronald P. ; Chan, Timothy A. ; Greenbaum, Benjamin D. ; Merghoub, Taha ; Leach, Steven D. ; Bassi, Claudio. / Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. In: Nature. 2017 ; Vol. 551, No. 7681. pp. 512-516.
@article{9b953ca323034bb4a5771ab8c5631932,
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 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.",
keywords = "HUMAN-MELANOMA, PD-1 BLOCKADE, MUC16, CELLS, DYNAMICS, ANTIGEN, TUMORS, MICE",
author = "Balachandran, {Vinod P.} and Marta Luksza and Zhao, {Julia N.} and Vladimir Makarov and Moral, {John Alec} and Romain Remark and Brian Herbst and Gokce Askan and Umesh Bhanot and Yasin Senbabaoglu and Wells, {Daniel K.} and Cary, {Charles Ian Ormsby} and Olivera Grbovic-Huezo and Marc Attiyeh and Benjamin Medina and Jennifer Zhang and Jennifer Loo and Joseph Saglimbeni and Mohsen Abu-Akeel and Roberta Zappasodi and Nadeem Riaz and Martin Smoragiewicz and Kelley, {Z. Larkin} and Olca Basturk and {Australian Pancreatic Cancer Genome Initiative} and Mithat Goenen and Levine, {Arnold J.} and Allen, {Peter J.} and Fearon, {Douglas T.} and Miriam Merad and Sacha Gnjatic and Iacobuzio-Donahue, {Christine A.} and Wolchok, {Jedd D.} and DeMatteo, {Ronald P.} and Chan, {Timothy A.} and Greenbaum, {Benjamin D.} and Taha Merghoub and Leach, {Steven D.} and Johns, {Amber L.} and Mead, {R. Scott} and Gill, {Anthony J.} and Chang, {David K.} and McKay, {Skye H.} and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Chou Angela and Humphris, {Jeremy L.} and Marina Pajic and Steinmann, {Angela M.} and Mehreen Arshi and Ali Drury and Danielle Froio and Ashleigh Morgan and Paul Timpson and Claire Vennin and Sean Warren and Mark Pinese and Jianmin Wu and Pinho, {Andreia V.} and Katherine Tucker and Lesley Andrews and Samra, {Jaswinder S.} and Jennifer Arena and Nick Pavlakis and High, {Hilda A.} and Anubhav Mittal and Biankin, {Andrew V.} and Peter Bailey and Sancha Martin and Musgrove, {Elizabeth A.} and Jones, {Marc D.} and Craig Nourse and Jamieson, {Nigel B.} and Alina Stoita and David Williams and Allan Spigellman and Nicola Waddell and Pearson, {John V.} and Ann-Marie Patch and Katia Nones and Felicity Newell and Pamela Mukhopadhyay and Venkateswar Addala and Stephen Kazakoff and Oliver Holmes and Conrad Leonard and Scott Wood and Christina Xu and Grimmond, {Sean M.} and Oliver Hofmann and Wilson, {Peter J.} and Angelika Christ and Tim Bruxner and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Annabel Goodwin and Cosman, {Peter H.} and Kasim Ismail and Chelsie O'Connor and Cooper, {Caroline L.} and Peter Grimison and Kench, {James G.} and Charbel Sandroussi and Lam, {Vincent W.} and Duncan McLeod and Nagrial, {Adnan M.} and Judy Kirk and Virginia James and Michael Texler and Cindy Forrest and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Nikolajs Zeps and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Clouston, {Andrew D.} and Patrick Martin and Andrew Barbour and O'Rourke, {Thomas J.} and Fawcett, {Jonathan W.} and Kellee Slater and Michael Hatzifotis and Peter Hodgkinson and Mehrdad Nikfarjam and Eshleman, {James R.} and Hruban, {Ralph H.} and Wolfgang, {Christopher L.} and Mary Hodgin and Aldo Scarpa and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi",
year = "2017",
month = "11",
day = "23",
doi = "10.1038/nature24462",
language = "English",
volume = "551",
pages = "512--516",
journal = "Nature",
issn = "1476-4687",
publisher = "Nature Publishing Groups",
number = "7681",

}

Balachandran, VP, Luksza, M, Zhao, JN, Makarov, V, Moral, JA, Remark, R, Herbst, B, Askan, G, Bhanot, U, Senbabaoglu, Y, Wells, DK, Cary, CIO, Grbovic-Huezo, O, Attiyeh, M, Medina, B, Zhang, J, Loo, J, Saglimbeni, J, Abu-Akeel, M, Zappasodi, R, Riaz, N, Smoragiewicz, M, Kelley, ZL, Basturk, O, Australian Pancreatic Cancer Genome Initiative, Goenen, M, Levine, AJ, Allen, PJ, Fearon, DT, Merad, M, Gnjatic, S, Iacobuzio-Donahue, CA, Wolchok, JD, DeMatteo, RP, Chan, TA, Greenbaum, BD, Merghoub, T, Leach, SD & Bassi, C 2017, 'Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer', Nature, vol. 551, no. 7681, pp. 512-516. https://doi.org/10.1038/nature24462

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. / Balachandran, Vinod P.; Luksza, Marta; Zhao, Julia N.; Makarov, Vladimir; Moral, John Alec; Remark, Romain; Herbst, Brian; Askan, Gokce; Bhanot, Umesh; Senbabaoglu, Yasin; Wells, Daniel K.; Cary, Charles Ian Ormsby; Grbovic-Huezo, Olivera; Attiyeh, Marc; Medina, Benjamin; Zhang, Jennifer; Loo, Jennifer; Saglimbeni, Joseph; Abu-Akeel, Mohsen; Zappasodi, Roberta; Riaz, Nadeem; Smoragiewicz, Martin; Kelley, Z. Larkin; Basturk, Olca; Australian Pancreatic Cancer Genome Initiative; Goenen, Mithat; Levine, Arnold J.; Allen, Peter J.; Fearon, Douglas T.; Merad, Miriam; Gnjatic, Sacha; Iacobuzio-Donahue, Christine A.; Wolchok, Jedd D.; DeMatteo, Ronald P.; Chan, Timothy A.; Greenbaum, Benjamin D.; Merghoub, Taha; Leach, Steven D.; Bassi, Claudio.

In: Nature, Vol. 551, No. 7681, 23.11.2017, p. 512-516.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

AU - Balachandran, Vinod P.

AU - Luksza, Marta

AU - Zhao, Julia N.

AU - Makarov, Vladimir

AU - Moral, John Alec

AU - Remark, Romain

AU - Herbst, Brian

AU - Askan, Gokce

AU - Bhanot, Umesh

AU - Senbabaoglu, Yasin

AU - Wells, Daniel K.

AU - Cary, Charles Ian Ormsby

AU - Grbovic-Huezo, Olivera

AU - Attiyeh, Marc

AU - Medina, Benjamin

AU - Zhang, Jennifer

AU - Loo, Jennifer

AU - Saglimbeni, Joseph

AU - Abu-Akeel, Mohsen

AU - Zappasodi, Roberta

AU - Riaz, Nadeem

AU - Smoragiewicz, Martin

AU - Kelley, Z. Larkin

AU - Basturk, Olca

AU - Australian Pancreatic Cancer Genome Initiative

AU - Goenen, Mithat

AU - Levine, Arnold J.

AU - Allen, Peter J.

AU - Fearon, Douglas T.

AU - Merad, Miriam

AU - Gnjatic, Sacha

AU - Iacobuzio-Donahue, Christine A.

AU - Wolchok, Jedd D.

AU - DeMatteo, Ronald P.

AU - Chan, Timothy A.

AU - Greenbaum, Benjamin D.

AU - Merghoub, Taha

AU - Leach, Steven D.

AU - Johns, Amber L.

AU - Mead, R. Scott

AU - Gill, Anthony J.

AU - Chang, David K.

AU - McKay, Skye H.

AU - Chantrill, Lorraine A.

AU - Chin, Venessa T.

AU - Angela, Chou

AU - Humphris, Jeremy L.

AU - Pajic, Marina

AU - Steinmann, Angela M.

AU - Arshi, Mehreen

AU - Drury, Ali

AU - Froio, Danielle

AU - Morgan, Ashleigh

AU - Timpson, Paul

AU - Vennin, Claire

AU - Warren, Sean

AU - Pinese, Mark

AU - Wu, Jianmin

AU - Pinho, Andreia V.

AU - Tucker, Katherine

AU - Andrews, Lesley

AU - Samra, Jaswinder S.

AU - Arena, Jennifer

AU - Pavlakis, Nick

AU - High, Hilda A.

AU - Mittal, Anubhav

AU - Biankin, Andrew V.

AU - Bailey, Peter

AU - Martin, Sancha

AU - Musgrove, Elizabeth A.

AU - Jones, Marc D.

AU - Nourse, Craig

AU - Jamieson, Nigel B.

AU - Stoita, Alina

AU - Williams, David

AU - Spigellman, Allan

AU - Waddell, Nicola

AU - Pearson, John V.

AU - Patch, Ann-Marie

AU - Nones, Katia

AU - Newell, Felicity

AU - Mukhopadhyay, Pamela

AU - Addala, Venkateswar

AU - Kazakoff, Stephen

AU - Holmes, Oliver

AU - Leonard, Conrad

AU - Wood, Scott

AU - Xu, Christina

AU - Grimmond, Sean M.

AU - Hofmann, Oliver

AU - Wilson, Peter J.

AU - Christ, Angelika

AU - Bruxner, Tim

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - Pavey, Darren

AU - Das, Amitabha

AU - Goodwin, Annabel

AU - Cosman, Peter H.

AU - Ismail, Kasim

AU - O'Connor, Chelsie

AU - Cooper, Caroline L.

AU - Grimison, Peter

AU - Kench, James G.

AU - Sandroussi, Charbel

AU - Lam, Vincent W.

AU - McLeod, Duncan

AU - Nagrial, Adnan M.

AU - Kirk, Judy

AU - James, Virginia

AU - Texler, Michael

AU - Forrest, Cindy

AU - Epari, Krishna P.

AU - Ballal, Mo

AU - Fletcher, David R.

AU - Mukhedkar, Sanjay

AU - Zeps, Nikolajs

AU - Beilin, Maria

AU - Feeney, Kynan

AU - Nguyen, Nan Q.

AU - Ruszkiewicz, Andrew R.

AU - Worthley, Chris

AU - Chen, John

AU - Brooke-Smith, Mark E.

AU - Papangelis, Virginia

AU - Clouston, Andrew D.

AU - Martin, Patrick

AU - Barbour, Andrew

AU - O'Rourke, Thomas J.

AU - Fawcett, Jonathan W.

AU - Slater, Kellee

AU - Hatzifotis, Michael

AU - Hodgkinson, Peter

AU - Nikfarjam, Mehrdad

AU - Eshleman, James R.

AU - Hruban, Ralph H.

AU - Wolfgang, Christopher L.

AU - Hodgin, Mary

AU - Scarpa, Aldo

AU - Lawlor, Rita T.

AU - Beghelli, Stefania

AU - Corbo, Vincenzo

AU - Scardoni, Maria

AU - Bassi, Claudio

PY - 2017/11/23

Y1 - 2017/11/23

N2 - 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.

AB - 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.

KW - HUMAN-MELANOMA

KW - PD-1 BLOCKADE

KW - MUC16

KW - CELLS

KW - DYNAMICS

KW - ANTIGEN

KW - TUMORS

KW - MICE

UR - http://www.scopus.com/inward/record.url?scp=85034815842&partnerID=8YFLogxK

U2 - 10.1038/nature24462

DO - 10.1038/nature24462

M3 - Article

VL - 551

SP - 512

EP - 516

JO - Nature

T2 - Nature

JF - Nature

SN - 1476-4687

IS - 7681

ER -

Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA, Remark R et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017 Nov 23;551(7681):512-516. https://doi.org/10.1038/nature24462