title: Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.
abstract: Purpose:Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy.Experimental Design:A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance.Results:PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers, and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neoantigen burden, immunologic, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunologic therapy approaches. In addition, a subtype with low levels of neoantigens and minimal lymphocyte infiltrate was associated with improved overall survival.Conclusions:The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC.Clin Cancer Res; 23(15); 4429-40. ©2017 AACR.
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.|Department of Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Paris
authors.initials: P
authors.lastname: Vail
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Uthra
authors.initials: U
authors.lastname: Balaji
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Hoai
authors.initials: H
authors.lastname: Ngo
authors.affiliation: HTG Molecular Diagnostics, Tucson, Arizona.
authors.forename: Ihab W
authors.initials: IW
authors.lastname: Botros
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York.|Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Riaz
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Vinod
authors.initials: V
authors.lastname: Balachandran
authors.affiliation: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Steven
authors.initials: S
authors.lastname: Leach
authors.affiliation: HTG Molecular Diagnostics, Tucson, Arizona.
authors.forename: Debrah M
authors.initials: DM
authors.lastname: Thompson
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York.|Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas. awitki@email.arizona.edu.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.|Department of Medicine, University of Arizona, Tucson, Arizona.|Department of Pathology, University of Arizona, Tucson, Arizona.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D000073359:Exome Sequencing; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D060890:B7-H1 Antigen; D015415:Biomarkers; D000098902:CD163 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D011956:Receptors, Cell Surface