title: Immune Cytolytic Activity Stratifies Molecular Subsets of Human Pancreatic Cancer.
abstract: Purpose:Immunotherapy has the potential to improve the dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials, including those with single-agent PD-1 or PD-L1 inhibition, have been disappointing. Our aim was to examine the immune landscape of PDA as it relates to aspects of tumor biology, including neoepitope burden.Experimental Design:We used publicly available expression data from 134 primary resection PDA samples from The Cancer Genome Atlas to stratify patients according to a cytolytic T-cell activity expression index. We correlated cytolytic immune activity with mutational, structural, and neoepitope features of the tumor.Results:Human PDA displays a range of intratumoral cytolytic T-cell activity. PDA tumors with low cytolytic activity exhibited significantly increased copy number alterations, including recurrent amplifications ofMYCandNOTCH2and recurrent deletions and mutations ofCDKN2A/BIn sharp contrast to other tumor types, high cytolytic activity in PDA did not correlate with increased mutational burden or neoepitope load (MHC class I and class II). Cytolytic-high tumors exhibited increased expression of multiple immune checkpoint genes compared to cytolytic-low tumors, except forPD-L1expression, which was uniformly low.Conclusions:These data identify a subset of human PDA with high cytolytic T-cell activity. Rather than being linked to mutation burden or neoepitope load, immune activation indices in PDA were inversely linked to genomic alterations, suggesting that intrinsic oncogenic processes drive immune inactivity in human PDA. Furthermore, these data highlight the potential importance of immune checkpoints other than PD-L1/PD-1 as therapeutic targets in this lethal disease.Clin Cancer Res; 23(12); 3129-38. ©2016 AACR.
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Balli
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rech
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. rhv@exchange.upenn.edu bstanger@exchange.upenn.edu.|Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. rhv@exchange.upenn.edu bstanger@exchange.upenn.edu.|Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000939:Epitopes