Utilizing sets of pancreatic cancer patients who differed significantly in median survival (6 years vs. 0.8 months), Balachandran et al. demonstrated that the long-term survivors exhibited superiority for multiple markers of immune activation, and that neoantigen load and either CD8+ T cell infiltration or TCR polyclonality were correlated with longer survival. A neoantigen quality score, based on molecular mimicry to known epitopes from infectious agents, independently stratified patients, suggesting a possible evolutionary dynamic sculpting the TCR repertoire.
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.
Author Info: (1) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Canc
Author Info: (1) 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. (2) The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA. (3) 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. (4) 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. (5) 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. (6) Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (7) David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (8) 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. (9) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (10) Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA. (11) Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. (12) Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. (13) David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (14) 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. (15) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (16) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (17) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (18) David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (19) Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA. (20) Swim Across America/Ludwig Collaborative Laboratory, New York, New York, USA. (21) 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. (22) Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK. (23) Cold Spring Harbor Laboratory, New York, New York, USA. Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA. (24) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (25) Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (26) The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey, USA. (27) 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. (28) Cold Spring Harbor Laboratory, New York, New York, USA. Department of Microbiology and Immunology, Weill Cornell Medical School, New York, New York, USA. (29) Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (30) Tisch Cancer Institute, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. (31) 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. (32) 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. (33) 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. (34) 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. (35) 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. (36) 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. (37) 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.
