title: Genomic Profiling of Patient-Derived Xenografts for Lung Cancer IdentifiesB2MInactivation Impairing Immunorecognition.
abstract: Purpose:We aimed to maximize the performance of detecting genetic alterations in lung cancer using high-throughput sequencing for patient-derived xenografts (PDXs).Experimental Design:We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of β2-microglobulin (B2M), a component of the HLA class-I complex.Results:We identified alterations in genes involved in various functions, such asB2Minvolved in immunosurveillance. We extended the mutational analysis ofB2Mto about 230 lung cancers. Five percent of the lung cancers carried somatic mutations, most of which impaired the correct formation of the HLA-I complex. We also report that genes such asCALR, PDIA3, andTAP1, which are involved in the maturation of the HLA-I complex, are altered in lung cancer. By gene expression microarrays, we observed that restitution ofB2Min lung cancer cells upregulated targets of IFNα/IFNγ. Furthermore, one third of the lung cancers lacked the HLA-I complex, which was associated with lower cytotoxic CD8+lymphocyte infiltration. The levels of B2M and HLA-I proteins correlated with those of PD-L1. Finally, a deficiency in HLA-I complex and CD8+infiltration tended to correlate with reduced survival of patients with lung cancer treated with anti-PD-1/anti-PD-L1.Conclusions:Here, we report recurrent inactivation ofB2Min lung cancer. These observations, coupled with the mutations found atCALR, PDIA3, andTAP1, and the downregulation of the HLA-I complex, indicate that an abnormal immunosurveillance axis contributes to lung cancer development. Finally, our observations suggest that an impaired HLA-I complex affects the response to anti-PD-1/anti-PD-L1 therapies.Clin Cancer Res; 23(12); 3203-13. ©2016 AACR.
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Pol
authors.initials: P
authors.lastname: Gimenez-Xavier
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Pros
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.|Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA) and Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pajares
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Moro
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Pathology Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez-Lopez
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rubio-Camarillo
authors.affiliation: Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Martinez-Martí
authors.affiliation: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.affiliation: Thoracic Oncology, Hospital Universitario de La Ribera, Alzira, Valencia, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Galbis
authors.affiliation: Department of Medical Oncology, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Nadal
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pisano
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.affiliation: Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.|Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA) and Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.|Xenopat S.L. Business Bioincubator Bellvitge Health Science Campus, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. mscespedes@idibell.cat.
authors.forename: Montse
authors.initials: M
authors.lastname: Sanchez-Cespedes
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D000073359:Exome Sequencing; D023041:Xenograft Model Antitumor Assays; D001613:beta 2-Microglobulin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015395:Histocompatibility Antigens Class I; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D001613:beta 2-Microglobulin