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

Autor: Balachandran VP; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Łuksza M; The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA., Zhao JN; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Makarov V; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Moral JA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Remark R; Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Herbst B; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Askan G; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Bhanot U; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Senbabaoglu Y; Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA., Wells DK; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA., Cary CIO; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA., Grbovic-Huezo O; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Attiyeh M; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Medina B; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Zhang J; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Loo J; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Saglimbeni J; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Abu-Akeel M; Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA., Zappasodi R; Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA., Riaz N; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Smoragiewicz M; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK., Kelley ZL; Cold Spring Harbor Laboratory, New York, New York, USA.; Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA., Basturk O; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Gönen M; Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Levine AJ; The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA., Allen PJ; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Fearon DT; Cold Spring Harbor Laboratory, New York, New York, USA.; Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA., Merad M; Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Gnjatic S; Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Iacobuzio-Donahue CA; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Wolchok JD; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA.; Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Weill Cornell Medical College, Cornell University, New York, New York, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA., DeMatteo RP; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Chan TA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Greenbaum BD; 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., Merghoub T; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Leach SD; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Dartmouth Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
Jazyk: angličtina
Zdroj: Nature [Nature] 2017 Nov 23; Vol. 551 (7681), pp. 512-516. Date of Electronic Publication: 2017 Nov 08.
DOI: 10.1038/nature24462
Abstrakt: 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.
Databáze: MEDLINE
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