Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition
Por:
Pereira C, Gimenez-Xavier P, Pros E, Pajares MJ, Moro M, Gomez A, Navarro A, Condom E, Moran S, Gomez-Lopez G, Graña O, Rubio-Camarillo M, Martinez-Martí A, Yokota J, Carretero J, Galbis JM, Nadal E, Pisano D, Sozzi G, Felip E, Montuenga LM, Roz L, Villanueva A and Sanchez-Cespedes M
Publicada:
15 jun 2017
Resumen:
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 beta 2-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 IFN alpha/IFN gamma. 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. (C) 2016 AACR.
Filiaciones:
Pereira C:
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Gimenez-Xavier P:
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Pros E:
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Pajares MJ:
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
Moro M:
Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Gomez A:
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Navarro A:
Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Condom E:
Pathology Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain
Moran S:
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Gomez-Lopez G:
Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
Graña O:
Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
Rubio-Camarillo M:
Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
Martinez-Martí A:
Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Yokota J:
Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain
Carretero J:
Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
:
Thoracic Oncology, Hospital Universitario de La Ribera, Alzira, Valencia, Spain
Nadal E:
Department of Medical Oncology, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
Pisano D:
Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain
Sozzi G:
Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Felip E:
Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Montuenga LM:
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
Roz L:
Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Villanueva A:
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
Sanchez-Cespedes M:
Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
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