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GENETIC ALTERATIONS INVOLVING PROGRAMMED DEATH LIGANDS IN EPSTEIN-BARR VIRUS-ASSOCIATED LYMPHOMAS
Author(s): ,
Keisuke Kataoka
Affiliations:
Department of Pathology and Tumor Biology,Kyoto University,Kyoto,Japan
,
Miyoshi Hiroaki
Affiliations:
Department of Pathology,Kurume University School of Medicine,Kurume,Japan
,
Seiji Sakata
Affiliations:
Pathology Project for Molecular Targets,Cancer Institute,Tokyo,Japan
,
Akito Dobashi
Affiliations:
Pathology Project for Molecular Targets,Cancer Institute,Tokyo,Japan
,
Lucile Couronné
Affiliations:
Clinical Hematology,Imagine Institute,Paris,France
,
Yasunori Kogure
Affiliations:
Department of Pathology and Tumor Biology,Kyoto University,Kyoto,Japan
,
Yasuharu Sato
Affiliations:
Department of Pathology,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama,Japan
,
Kenji Nishida
Affiliations:
Department of Pathology,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama,Japan
,
Yuichi Shiraishi
Affiliations:
Laboratory of DNA Information Analysis,The University of Tokyo,Tokyo,Japan
,
Hiroko Tanaka
Affiliations:
Laboratory of DNA Information Analysis,The University of Tokyo,Tokyo,Japan
,
Kenichi Chiba
Affiliations:
Laboratory of DNA Information Analysis,The University of Tokyo,Tokyo,Japan
,
Yosaku Watatani
Affiliations:
Department of Pathology and Tumor Biology,Kyoto University,Kyoto,Japan
,
Yusuke Shiozawa
Affiliations:
Department of Pathology and Tumor Biology,Kyoto University,Kyoto,Japan
,
Kenichi Yoshida
Affiliations:
Department of Pathology and Tumor Biology,Kyoto University,Kyoto,Japan
,
Masashi Sanada
Affiliations:
Department of Advanced Diagnosis,Nagoya Medical Center,Nagoya,Japan
,
Motohiro Kato
Affiliations:
Department of Pediatric Hematology and Oncology Research,National Centre for Child Health and Development,Tokyo,Japan
,
Satoru Miyano
Affiliations:
Laboratory of DNA Information Analysis,The University of Tokyo,Tokyo,Japan
,
Yasunori Ota
Affiliations:
Department of Pathology,Toranomon Hospital,Tokyo,Japan
,
Koji Izutsu
Affiliations:
Department of Hematology,Toranomon Hospital,Tokyo,Japan
,
Tadashi Yoshino
Affiliations:
Department of Pathology,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama,Japan
,
Olivier Hermine
Affiliations:
Clinical Hematology,Imagine Institute,Paris,France
,
Kengo Takeuchi
Affiliations:
Pathology Project for Molecular Targets,Cancer Institute,Tokyo,Japan
,
Koichi Ohshima
Affiliations:
Department of Pathology,Kurume University School of Medicine,Kurume,Japan
Seishi Ogawa
Affiliations:
Department of Pathology and Tumor Biology,Kyoto University,Kyoto,Japan
(Abstract release date: 05/18/17) EHA Library. Kataoka K. 06/23/17; 181411; S124
Dr. Keisuke Kataoka
Dr. Keisuke Kataoka
Contributions
Abstract

Abstract: S124

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:30 - 11:45

Location: Room N101

Background
Checkpoint blockade using anti-PD-1/PD-L1 antibodies is a highly promising therapy for cancer, frequently showing dramatic anti-tumor responses in a wide variety of tumor types. Particularly, an exceptional response to anti-PD-1 antibodies has been demonstrated for classical Hodgkin lymphoma (HL), which is characterized by frequent copy number gains/amplifications involving PD-L1 and/or PD-L2, suggesting a close link between PD-L1/PD-L2 genetic alterations and the therapeutic response to these agents. Recently, we have reported frequent structural variations (SVs) in adult T-cell leukemia/lymphoma (ATL) caused by human T-cell leukemia virus type-1 (HTLV-1). These SVs invariably affect 3′-untranslated region (UTR) of PD-L1, leading to prominent PD-L1 overexpression. Providing that viral antigens induce potent cellular immunity to virally infected cells, we hypothesized that a deregulated PD-1/PD-L1 axis might play a critical role in evasion from anti-viral immunity before these cells are clonally selected for neoplastic proliferation.

Aims
Epstein-Barr virus is a DNA tumor virus closely associated with various human cancers, including B- and natural killer (NK)/T-cell lymphomas, in which genetic alterations involving PD-L1/PD-L2 may also be relevant to cancer evolution. In this study, to assess this hypothesis, we interrogated a variety of lymphomas for genetic abnormalities affecting PD-L1 and PD-L2, especially focusing on EBV-associated lymphomas.

Methods
SVs and other genetic lesions affecting PD-L1 and PD-L2 were analyzed using targeted-capture sequencing with cRNA baits designed for capturing the entire sequences of PD-L1 and PD-L2 genes, including exons, introns, and 5′- and 3′-UTRs. More than 400 samples were analyzed obtained from different subtypes of non-Hodgkin lymphomas, including EBV-associated lymphomas, such as EBV-positive diffuse large B-cell lymphoma (DLBCL) and NK/T-cell malignancies.

Results
SVs and/or focal copy number gains involving PD ligands were successfully detected in various B-cell and T/NK-cell lymphomas, albeit at generally low frequencies (< 10%). These lesions were the most frequently observed in PMBCL, accounting for more than 60% of the cases. Of note, high frequency (17−57%) of PD-L1/PD-L2-involving abnormalities were observed in mature NK/T-cell neoplasms, including extranodal NK/T-cell lymphoma, aggressive NK cell leukemia, and EBV-positive T-cell lymphoproliferative disorder, all of which were positive for EBV. Moreover, a substantial proportion (22%) of EBV-positive DLBCL cases possessed these lesions, whereas EBV-negative cases rarely exhibited these alterations (2%, P<0.01). For both PD-L1 and PD-L2 SVs, despite a large diversity of SV type (deletions, inversions, tandem duplications, and translocations), most of SVs resulted in 3’-UTR truncation, while the replacement of PD-L1 or PD-L2 promoter with an ectopic regulatory element was rarely observed. Interestingly, PD-L1 SVs were detected in both B- and T-cell lymphomas, whereas PD-L2 SVs were found exclusively in B-cell lymphomas.

Conclusion
We delineate the entire picture of genetic alterations involving PD ligands, and confirm the close association between these lesions and EBV-associated lymphomas. Our finding help to understand their pathogenesis and develop a new diagnostic strategy to identify patients who potentially benefit from PD-1/PD-L1 blockade therapy in non-Hodgkin lymphomas.

Session topic: 18. Non-Hodgkin & Hodgkin lymphoma - Biology

Keyword(s): Non-Hodgkin's lymphoma, Epstein barr virus

Abstract: S124

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:30 - 11:45

Location: Room N101

Background
Checkpoint blockade using anti-PD-1/PD-L1 antibodies is a highly promising therapy for cancer, frequently showing dramatic anti-tumor responses in a wide variety of tumor types. Particularly, an exceptional response to anti-PD-1 antibodies has been demonstrated for classical Hodgkin lymphoma (HL), which is characterized by frequent copy number gains/amplifications involving PD-L1 and/or PD-L2, suggesting a close link between PD-L1/PD-L2 genetic alterations and the therapeutic response to these agents. Recently, we have reported frequent structural variations (SVs) in adult T-cell leukemia/lymphoma (ATL) caused by human T-cell leukemia virus type-1 (HTLV-1). These SVs invariably affect 3′-untranslated region (UTR) of PD-L1, leading to prominent PD-L1 overexpression. Providing that viral antigens induce potent cellular immunity to virally infected cells, we hypothesized that a deregulated PD-1/PD-L1 axis might play a critical role in evasion from anti-viral immunity before these cells are clonally selected for neoplastic proliferation.

Aims
Epstein-Barr virus is a DNA tumor virus closely associated with various human cancers, including B- and natural killer (NK)/T-cell lymphomas, in which genetic alterations involving PD-L1/PD-L2 may also be relevant to cancer evolution. In this study, to assess this hypothesis, we interrogated a variety of lymphomas for genetic abnormalities affecting PD-L1 and PD-L2, especially focusing on EBV-associated lymphomas.

Methods
SVs and other genetic lesions affecting PD-L1 and PD-L2 were analyzed using targeted-capture sequencing with cRNA baits designed for capturing the entire sequences of PD-L1 and PD-L2 genes, including exons, introns, and 5′- and 3′-UTRs. More than 400 samples were analyzed obtained from different subtypes of non-Hodgkin lymphomas, including EBV-associated lymphomas, such as EBV-positive diffuse large B-cell lymphoma (DLBCL) and NK/T-cell malignancies.

Results
SVs and/or focal copy number gains involving PD ligands were successfully detected in various B-cell and T/NK-cell lymphomas, albeit at generally low frequencies (< 10%). These lesions were the most frequently observed in PMBCL, accounting for more than 60% of the cases. Of note, high frequency (17−57%) of PD-L1/PD-L2-involving abnormalities were observed in mature NK/T-cell neoplasms, including extranodal NK/T-cell lymphoma, aggressive NK cell leukemia, and EBV-positive T-cell lymphoproliferative disorder, all of which were positive for EBV. Moreover, a substantial proportion (22%) of EBV-positive DLBCL cases possessed these lesions, whereas EBV-negative cases rarely exhibited these alterations (2%, P<0.01). For both PD-L1 and PD-L2 SVs, despite a large diversity of SV type (deletions, inversions, tandem duplications, and translocations), most of SVs resulted in 3’-UTR truncation, while the replacement of PD-L1 or PD-L2 promoter with an ectopic regulatory element was rarely observed. Interestingly, PD-L1 SVs were detected in both B- and T-cell lymphomas, whereas PD-L2 SVs were found exclusively in B-cell lymphomas.

Conclusion
We delineate the entire picture of genetic alterations involving PD ligands, and confirm the close association between these lesions and EBV-associated lymphomas. Our finding help to understand their pathogenesis and develop a new diagnostic strategy to identify patients who potentially benefit from PD-1/PD-L1 blockade therapy in non-Hodgkin lymphomas.

Session topic: 18. Non-Hodgkin & Hodgkin lymphoma - Biology

Keyword(s): Non-Hodgkin's lymphoma, Epstein barr virus

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