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The rare people who survive pancreatic cancer for years have tumours carrying both many mutation-made target proteins and plenty of killer T cells, and the quality of those targets, some resembling germ proteins, predicts long survival.
Genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics and functional assays were used to identify T-cell antigens in long-term survivors of pancreatic cancer. Whole-exome sequencing with in silico neoantigen prediction showed that tumours with both the highest neoantigen number and the most abundant CD8 T-cell infiltrates, but neither alone, stratified the longest survival. A neoantigen quality fitness model giving greater immunogenicity to neoantigens with differential presentation and homology to infectious disease peptides identified long-term survivors in two independent datasets, whereas a quantity model did not; MUC16 neoantigens featured. Intratumoural and lasting circulating T-cell reactivity to high-quality and MUC16 neoantigens was detected, and high-quality neoantigenic clones were selectively lost on metastatic progression, consistent with immunoediting.
It is the proof that T cells can control pancreatic cancer in some people, and the scientific basis for the personalised neoantigen vaccines now in trials.
Shares Vinod P. Balachandran, Neoantigen, Tumour mutational burden (TMB), Nature.
Shares Vinod P. Balachandran, Neoantigen, Nature, Personalised neoantigen (mRNA) vaccines.
Shares Nature, Whole-exome & whole-genome sequencing, Memorial Sloan Kettering Cancer Center, Pancreatic ductal adenocarcinoma.
Shares Antigen presentation & immune editing, Neoantigen, Personalised neoantigen (mRNA) vaccines, Memorial Sloan Kettering Cancer Center.
Shares Immune exclusion, Nature.
Shares Neoantigen, Tumour mutational burden (TMB), Memorial Sloan Kettering Cancer Center.
Shares Vinod P. Balachandran, Personalised neoantigen (mRNA) vaccines, Memorial Sloan Kettering Cancer Center, Pancreatic ductal adenocarcinoma.