title: Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma.
abstract: Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues.
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Forget
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Francis A San
authors.initials: FA
authors.lastname: Lucas
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Hector A
authors.initials: HA
authors.lastname: Alvarez
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Cara
authors.initials: C
authors.lastname: Haymaker
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Chattopadhyay
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016000:Cluster Analysis; D016208:Databases, Factual; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D000951:Antigens, Neoplasm; D052247:Nitric Oxide Synthase Type II