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      Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition.

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          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 as B2M involved in immunosurveillance. We extended the mutational analysis of B2M to 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 as CALR, PDIA3, and TAP1, which are involved in the maturation of the HLA-I complex, are altered in lung cancer. By gene expression microarrays, we observed that restitution of B2M in 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 of B2M in lung cancer. These observations, coupled with the mutations found at CALR, PDIA3, and TAP1, 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.

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          Author and article information

          Journal
          Clin. Cancer Res.
          Clinical cancer research : an official journal of the American Association for Cancer Research
          American Association for Cancer Research (AACR)
          1078-0432
          1078-0432
          Jun 15 2017
          : 23
          : 12
          Affiliations
          [1 ] Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
          [2 ] Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
          [3 ] Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA) and Navarra's Health Research Institute (IDISNA), Pamplona, Spain.
          [4 ] Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
          [5 ] Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
          [6 ] Pathology Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
          [7 ] Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
          [8 ] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
          [9 ] Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.
          [10 ] Thoracic Oncology, Hospital Universitario de La Ribera, Alzira, Valencia, Spain.
          [11 ] Department of Medical Oncology, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
          [12 ] Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
          [13 ] Xenopat S.L. Business Bioincubator Bellvitge Health Science Campus, Hospitalet de Llobregat, Barcelona, Spain.
          [14 ] Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. mscespedes@idibell.cat.
          Article
          1078-0432.CCR-16-1946
          10.1158/1078-0432.CCR-16-1946
          28302866

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