Details

Autor(en) / Beteiligte

• Balachandran, Vinod P.
• Łuksza, 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
• Gönen, 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.

Titel

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

Ist Teil von

• Nature (London), 2017-11, Vol.551 (7681), p.512-516

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• The analysis of T-cell antigens in long-term survivors of pancreatic ductal adenocarcinoma suggests that neoantigen immunogenicity and quality, not purely quantity, correlate with survival. Neoantigen quality over quantity A small percentage of patients with pancreatic cancer survive beyond five years, but the reason for their relative longevity remains uncertain. In this retrospective analysis, Vinod Balachandran et al . evaluate the immune mechanisms of long-term survival in human pancreatic cancer. The analysis shows that survival correlates with high mutation load in conjunction with increased infiltration of cytolytic T cells and polyclonal T-cell responses and that mutations at the tumour antigen MUC16 locus are enriched in long-term survivors. Additionally, patients with high predicted neoantigen–microbial cross-reactivity scores tended to live longest. The authors provide evidence that the quality rather than quantity of neoantigens determines survival. 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 1 , 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.