Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition
| العنوان: | Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition |
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| المؤلفون: | Alberto Villanueva, Sebastian Moran, Maria J. Pajares, Massimo Moro, Enriqueta Felip, Osvaldo Graña, Julian Carretero, Alejandro Navarro, Pol Gimenez-Xavier, Luis M. Montuenga, Jun Yokota, Enric Condom, Luca Roz, David G. Pisano, Eva Pros, Gabriella Sozzi, Montse Sanchez-Cespedes, Alex Martinez-Marti, Carolina Pereira, Ernest Nadal, Miriam Rubio-Camarillo, Gonzalo Gómez-López, Jose M Galbis, Antonio Gomez |
| المصدر: | Clinical Cancer Research. 23:3203-3213 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Lung, Human leukocyte antigen, Biology, medicine.disease, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Oncology, Downregulation and upregulation, Immunology, medicine, Cancer research, Cytotoxic T cell, Lung cancer, Exome sequencing, CD8 |
| الوصف: | 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. |
| تدمد: | 1557-3265 1078-0432 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::b03846d467f468b965f6ee18fa887aa3 https://doi.org/10.1158/1078-0432.ccr-16-1946 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........b03846d467f468b965f6ee18fa887aa3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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