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Zhao M, Wang L, Wang X, He J, Yu K, Li D. Non-neoplastic cells as prognostic biomarkers in diffuse large B-cell lymphoma: A system review and meta-analysis. TUMORI JOURNAL 2024; 110:227-240. [PMID: 38183180 DOI: 10.1177/03008916231221636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2024]
Abstract
The microenvironment of diffuse large B-cell lymphoma (DLBCL) is composed of various components, including immune cells and immune checkpoints, some of which have been correlated with the prognosis of DLBCL, but their results remain controversial. Therefore, we conducted a systematic review and meta-analysis to investigate the association between the microenvironment and prognosis in DLBCL. We searched PubMed, Web of Science, and EMBASE for relevant articles between 2001 and 2022. Twenty-five studies involving 4495 patients with DLBCL were included in the analysis. This meta-analysis confirmed that high densities of Foxp3+Tregs and PD-1+T cells are good indicators for overall survival (OS) in DLBCL, while high densities of programmed cell death protein ligand1(PD-L1)-positive expression cells and T-cell immunoglobulin-and mucin domain-3-containing molecule 3 (TIM-3)-positive expression tumor-infiltrating cells (TILs) play a contrary role in OS. Additionally, higher numbers of T-cell intracytoplasmic antigen-1(TIA-1)-positive expression T cells imply better OS and progression-free survival (PFS), while high numbers of lymphocyte activation gene(LAG)-positive expression TILs predict bad OS and PFS. Various non-tumoral cells in the microenvironment play important roles in the prognosis of DLBCL.
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MESH Headings
- Humans
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/mortality
- Prognosis
- Tumor Microenvironment/immunology
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Affiliation(s)
- Min Zhao
- Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Pathology, Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center of Chongqing Medical University, Chongqing, China
| | - Lixing Wang
- Department of Pathology, Chongqing Medical University, Chongqing, China
| | - Xingyu Wang
- Department of Pathology, Chongqing Medical University, Chongqing, China
| | - Juan He
- Department of Pathology, Chongqing Medical University, Chongqing, China
| | - Kuai Yu
- Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center of Chongqing Medical University, Chongqing, China
- Department of Pathology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Dan Li
- Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Pathology, Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center of Chongqing Medical University, Chongqing, China
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Cin S, Aki SH, Elverdi T, Ozmen D, Salihoglu A. Is There an Immunohistochemical PD-L1 Cut-Off Point That Serves as a Prognostic Indicator for Large B-Cell Lymphomas? Diagnostics (Basel) 2024; 14:1167. [PMID: 38893691 PMCID: PMC11172057 DOI: 10.3390/diagnostics14111167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/15/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
The aim of this study is to investigate whether there is a cut-off value for PD-L1 expression in large B-cell lymphomas that predicts prognosis, and to clarify the relationship between PD-L1 expression and histopathological as well as clinical parameters. The study included a total of 130 patients who were diagnosed with large B-cell lymphoma at Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Pathology Department. Biopsy samples were assessed using the PD-L1 immunohistochemical antibody (Dako, 22C3 clone). The patients had a mean age of 54 ± 17 years, with a median age of 56 years. No statistically significant difference was observed between the groups in terms of survival when the 30% cut-off value was used. However, a noteworthy discrepancy in survival became apparent when the cut-off point was established at 70%. Among the diffuse large B-cell lymphoma-not otherwise specified (DLBCL-NOS) category, the activated B-cell-like (ABC-like) phenotype showed higher PD-L1 expression compared to the germinal center B-cell-like (GCB-like) phenotype. Immunohistochemical PD-L1 expression emerged as a prognostic factor, particularly significant in the ABC-like phenotype.
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Affiliation(s)
- Selcuk Cin
- Department of Pathology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey;
| | - Suat Hilal Aki
- Department of Pathology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey;
| | - Tugrul Elverdi
- Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34320 Istanbul, Turkey; (T.E.); (D.O.); (A.S.)
| | - Deniz Ozmen
- Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34320 Istanbul, Turkey; (T.E.); (D.O.); (A.S.)
| | - Ayse Salihoglu
- Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34320 Istanbul, Turkey; (T.E.); (D.O.); (A.S.)
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Atmış Ö, Neşe N, Aydoğdu İ, Alaca İ, Mavili HS, İşisağ A. The Prognostic Impact of Tumor Microenvironment and Checkpoint Blockade-Associated Molecules (PD-1, PD-L1, CD163 and CD14) in Nodal Diffuse Large B-cell Lymphoma, NOS. Indian J Hematol Blood Transfus 2024; 40:340-345. [PMID: 38708156 PMCID: PMC11065815 DOI: 10.1007/s12288-023-01667-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 05/01/2023] [Indexed: 05/07/2024] Open
Abstract
It is aimed to determine expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), CD163 and CD14 in diffuse large B-cell lymphomas (DLBCL), and whether these markers may predict prognosis in DLBCL cases. A total of 52 nodal DLBCL, NOS cases with no known extranodal involvement at the time of diagnosis were evaluated. PD-1, PD-L1, CD163, and CD14 were studied by immunohistochemistry. The relationships between the results and clinical and laboratory prognostic markers were investigated. It was observed that patients with PD-1 expression < 5 positive cells/HPF had worse overall survival. No significant relationship was found between survival and PD-L1, CD163 and CD14 expressions. In addition, cases that are > 60 years of age, that have Eastern Cooperative Oncology Group (ECOG) performance score ≥ 2, stage IV disease, high International Prognostic Index score score (≥ 3), elevation of LDH, low albumin level, low hemoglobin level, low peripheral blood lymphocyte count, high peripheral blood neutrophil/lymphocyte ratio, high peripheral blood platelet/lymphocyte ratio were found to have worse overall survival. It was concluded that in patients with low number of PD-1 positive tumor-infiltrating lymphocytes have low survival rates and therefore PD-1 expression may be useful in indicating prognosis.
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Affiliation(s)
- Ömer Atmış
- Department of Pathology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - Nalan Neşe
- Department of Pathology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - İsmet Aydoğdu
- Department of Hematology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - İlknur Alaca
- Department of Hematology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - Hanife Seda Mavili
- Department of Pathology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - Aydın İşisağ
- Department of Pathology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
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Slak TC, Miceska S, Gasljevic G, Boltezar L, Kloboves-Prevodnik V. The prognostic significance of programmed cell death protein 1 and its ligand on lymphoma cells and tumor-immune cells in diffuse large B-cell lymphoma, not otherwise specified. Radiol Oncol 2024; 58:99-109. [PMID: 38378036 PMCID: PMC10878775 DOI: 10.2478/raon-2024-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 11/25/2023] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type non-Hodgkin's lymphoma, where the treatment of relapsed/refractory cases is the major challenge. Programmed cell death protein 1 (PD-1) and its ligand PD-L1 play a crucial role in the negative regulation of the immune response against the disease. The aim of the study was to analyze the expression of PD-1 and PD-L1 on lymphoma cells (LCs) and tumor-immune cells (TICs) and to investigate their correlation with outcome. PATIENTS AND METHODS Samples from 283 patients diagnosed with DLBCL, NOS (both germinal center B cell like [GCB] and non-GCB subtypes) were included in the study. Expression of PD-1 and PD-L1 was determined using double immunohistochemical staining (D-IHC) for PD-1/PAX5 and PD-L1/PAX5 on tissue microarrays. LCs were highlighted by D-IHC to obtain more accurate results. Clinical data and histologic diagnoses were obtained from electronic data records. We correlated clinical characteristics, and PD-1 and PD-L1 expression on LCs and TICs with progression-free survival (PFS) and overall survival (OS). RESULTS Expression of PD-1 on TICs was observed in 38.4% and on LCs in 8.8% of cases, while PD-L1 was expressed on TICs in 46.8% and on LCs in 6.5% of cases. PD-L1 expression on LCs was more frequent in non-GCB subtype (p = 0.047). In addition, patients with PD-L1 expression on LCs had significantly shorter PFS (p = 0.015), and the expression retained significant in the multivariate model (p = 0.034). CONCLUSIONS PD-L1 was more frequently expressed in LCs of the non-GCB subtype. Additionally, PD-L1 in LCs may predict shorter PFS time. D-IHC staining for PD-L1/PAX5 is a feasible method to assess PD-L1 expression on LCs of DLBCL, NOS patients and can be used to identify patients who may benefit from targeted immunotherapy with checkpoint inhibitors.
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Affiliation(s)
- Teja Cas Slak
- Department of Cytopathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Simona Miceska
- Department of Cytopathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Gorana Gasljevic
- Department of Pathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Lucka Boltezar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Veronika Kloboves-Prevodnik
- Department of Cytopathology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
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Mangiaterra T, Alonso-Alonso R, Rabinovich A, De Dios Soler M, Galluzzo L, Soria M, Colli S, De Matteo E, Rodriguez Pinilla SM, Chabay P. Presence of Epstein-Barr virus (EBV) antigens detected by sensitive methods has no influence on local immune environment in diffuse large B cell lymphoma. Cancer Immunol Immunother 2024; 73:29. [PMID: 38280007 PMCID: PMC10821829 DOI: 10.1007/s00262-023-03617-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/16/2023] [Indexed: 01/29/2024]
Abstract
EBV+ diffuse large B cell lymphoma (DLBCL) not otherwise specified (NOS) is a new entity confirmed by the World Health Organization (WHO) in 2017. In this new entity, the virus may contribute to a tolerogenic microenvironment. Traces of the virus have been described in DLBCL with more sensitive methods, in cases that were originally diagnosed as negative. The aim of this study was to analyze the expression of immune response genes in the tumor microenvironment to disclose the role of the virus and its traces in DLBCL. In 48 DLBCL cases, the expression of immune response genes and the presence of molecules that induce tolerance, such as TIM3, LAG3 and PDL1 by immunohistochemistry (IHC), were studied. To broaden the study of the microenvironment, tumor-associated macrophages (TMAs) were also explored. No significant differences were observed in the expression of immune response genes in the EBV+ DLBCL and those cases that were EBV- DLBCL but that exhibited viral traces, assessed by ViewRNA assay. Only the EBV+ DLBCL cases displayed a significantly higher increase in the expression of CD8 and cytotoxic T cells detected by gene expression analysis, and of PDL1 in tumor cells and in the expression of CD68 in the tumor microenvironment detected by IHC, not observed in those cases with viral traces. The increase in CD8 and cytotoxic T cells, PDL1 and CD68 markers only in EBV+ DLBCL may indicate that traces of viral infection might not have influence in immune response markers.
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Affiliation(s)
- T Mangiaterra
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina
| | - R Alonso-Alonso
- Pathology Department, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - A Rabinovich
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina
| | - M De Dios Soler
- Pathology Division, Marie Curie Hospital, Buenos Aires, Argentina
| | - L Galluzzo
- Pathology Division, Prof. Dr. Juan P. Garrahan Hospital, Buenos Aires, Argentina
| | - M Soria
- Hematology Division, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina
| | - S Colli
- Pathology Division, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina
| | - E De Matteo
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina
- Pathology Division, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina
| | | | - P Chabay
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina.
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Zheng S, Ma J, Li J, Pang X, Ma M, Ma Z, Cui W. Lower PTEN may be associated with CD8+ T cell exhaustion in diffuse large B-cell lymphoma. Hum Immunol 2023; 84:551-560. [PMID: 37481380 DOI: 10.1016/j.humimm.2023.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 06/30/2023] [Accepted: 07/16/2023] [Indexed: 07/24/2023]
Abstract
Initially discovered in chronic viral infection and then extended to tumor, 'T-cell exhaustion' is a broad term describing the response of T cells to chronic antigen stimulation. By definition, whether T-cell exhaustion occurs in diffuse large B-cell lymphoma (DLBCL) remains largely unknown because little has been described. Here, the immune-suppressing checkpoint molecules involved in T-cell exhaustion, including PD-1, PD-L1, TIM-3 and TIGIT, whose expression levels were analyzed in DLBCL, were retrieved from the GEPIA database. Compared with the normal control, CD8A, TNFA, IFNG and GZMA were markedly elevated in DLBCL, indicating that infiltrated CD8+ T cells predominate in DLBCL. Meanwhile, inhibitory immune checkpoints, such as PD-1, PD-L1, TIGIT and TIM-3 were drastically higher in DLBCL. PTEN, WNT2 and DKK3 expression were also appraised. It was revealed that PTEN was lower in DLBCL, without being statistically significant. In contrast with PTEN, DKK3 and WNT2 were shown to be pronouncedly higher in DLBCL relative to the normal control. Prognostically, only TIGIT was found to be associated with overall survival in DLBCL. Collectively, all the data we curetted from the GEPIA and TIMER 2.0 databases explicitly indicate that CD8+ T cell exhaustion took place, which may be linked with lower PTEN in DLBCL. To the best of our knowledge, this is the first bioinformatic report explicitly proposing that CD8+ T cell exhaustion occurs in DLBCL, which may be associated with lower PTEN.
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Affiliation(s)
- Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, PR China
| | - Jiajia Ma
- The Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang, PR China
| | - Junna Li
- The Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang, PR China
| | - Xuelian Pang
- The Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang, PR China
| | - Mingfu Ma
- The Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang, PR China
| | - Zhiping Ma
- The Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang, PR China
| | - Wenli Cui
- The Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 830011 Urumqi, Xinjiang, PR China.
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Cai Y, Chen X, Lu T, Fang X, Ding M, Yu Z, Hu S, Liu J, Zhou X, Wang X. Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma. Int J Biol Sci 2023; 19:4627-4643. [PMID: 37781035 PMCID: PMC10535696 DOI: 10.7150/ijbs.85236] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/11/2023] [Indexed: 10/03/2023] Open
Abstract
Genomic instability is a significant driver of cancer. As the sensor of cytosolic DNA, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in regulating anti-tumor immunity and cell death. However, the role and regulatory mechanisms of STING in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we reported that sterile alpha motif and HD domain-containing protein 1 (SAMHD1) deficiency induced STING expression and inhibited tumor growth in DLBCL. High level of SAMHD1 was associated with poor prognosis in DLBCL patients. Down-regulation of SAMHD1 inhibited DLBCL cell proliferation both in vitro and in vivo. Moreover, we found that SAMHD1 deficiency induced DNA damage and promoted the expression of DNA damage adaptor STING. STING overexpression promoted the formation of Caspase 8/RIPK3/ASC, further leading to MLKL phosphorylation, Caspase 3 cleavage, and GSDME cleavage. Up-regulation of necroptotic, apoptotic, and pyroptotic effectors indicated STING-mediated PANoptosis. Finally, we demonstrated that the STING agonist, DMXAA, enhanced the efficacy of a PD-L1 inhibitor in DLBCL. Our findings highlight the important role of STING-mediated PANoptosis in restricting DLBCL progression and provide a potential strategy for enhancing the efficacy of immune checkpoint inhibitor agents in DLBCL.
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Affiliation(s)
- Yiqing Cai
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Xiaomin Chen
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Tiange Lu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Xiaosheng Fang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China
- Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China
- National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China
| | - Mengfei Ding
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Zhuoya Yu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Shunfeng Hu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Jiarui Liu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
| | - Xiangxiang Zhou
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China
- Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China
- National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China
- Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China
- National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China
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Brunner A, Willenbacher E, Willenbacher W, Zelger B, Zelger P, Huck CW, Pallua JD. Visible- and near-infrared hyperspectral imaging for the quantitative analysis of PD-L1+ cells in human lymphomas: Comparison with fluorescent multiplex immunohistochemistry. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 285:121940. [PMID: 36208576 DOI: 10.1016/j.saa.2022.121940] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/22/2022] [Accepted: 09/28/2022] [Indexed: 06/16/2023]
Abstract
INTRODUCTION We analyzed the expression of PD-L1 in human lymphomas using hyperspectral imaging (HSI) compared to visual assessment (VA) and conventional digital image analysis (DIA) to strengthen further the value of HSI as a tool for the evaluation of brightfield-based immunohistochemistry (IHC). In addition, fluorescent multiplex immunohistochemistry (mIHC) was used as a second detection method to analyze the impact of a different detection method. MATERIAL AND METHODS 18 cases (6 follicular lymphomas and 12 diffuse large B-cell lymphomas) were stained for PD-L1 by IHC and for PD-L1, CD3, and CD8 by fluorescent mIHC. The percentage of positively stained cells was evaluated with VA, HSI, and DIA for IHC and VA and DIA for mIHC. Results were compared between the different methods of detection and analysis. RESULTS An overall high concordance was found between VA, HSI, and DIA in IHC (Cohens Kappa = 0.810VA/HSI, 0.710 VA/DIA, and 0.516 HSI/DIA) and for VAmIHCversus DIAmIHC (Cohens Kappa = 0.894). Comparing IHC and mIHC general agreement differed depending on the methods compared but reached at most a moderate agreement (Coheńs Kappa between 0.250 and 0.483). This is reflected by the significantly higher percentage of PD-L1+ cells found with mIHC (pFriedman = 0.014). CONCLUSION Our study shows a good concordance for the different analysis methods. Compared to VA and DIA, HSI proved to be a reliable tool for assessing IHC. Understanding the regulation of PD-L1 expression will further enlighten the role of PD-L1 as a biomarker. Therefore it is necessary to develop an instrument, such as HSI, which can offer a reliable and objective evaluation of PD-L1 expression.
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Affiliation(s)
- A Brunner
- Innsbruck Medical University, Institute of Pathology, Neuropathology and Molecular Pathology, Innsbruck, Austria
| | - E Willenbacher
- Innsbruck Medical University, Internal Medicine. V, Hematology & Oncology, Innsbruck, Austria
| | - W Willenbacher
- Innsbruck Medical University, Internal Medicine. V, Hematology & Oncology, Innsbruck, Austria; Syndena GmbH, Connect to Cure, Karl-Kapferer-Straße 5, 6020 Innsbruck, Austria
| | - B Zelger
- Innsbruck Medical University, Institute of Pathology, Neuropathology and Molecular Pathology, Innsbruck, Austria
| | - P Zelger
- Innsbruck Medical University, University Clinic for Hearing, Voice and Speech Disorders, Anichstrasse 35, Innsbruck, Austria
| | - C W Huck
- University of Innsbruck, Institute of Analytical Chemistry and Radiochemistry, Innsbruck, Austria
| | - J D Pallua
- Innsbruck Medical University, Department of Traumatology and Orthopaedics, Innsbruck, Austria.
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9
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Said RHM, Hussein FF, El-Deeb AM. Immunohistochemical Expression of Programmed Death Ligand 1 in Oral Extranodal Diffuse Large B Cell Lymphoma. Eur J Dent 2022. [PMID: 35944575 DOI: 10.1055/s-0042-1747951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022] Open
Abstract
OBJECTIVE Lymphomas are the third most common cancer after squamous cell carcinoma and salivary gland tumors. Extranodal diffuse B cell lymphoma (DBCL) represents 30 to 58% of non-Hodgkin's lymphoma. One of the major problems of DBCL is the high likelihood of disease relapse following treatment. A recent trend in the treatment of diffuse large B cell lymphoma (DLBCL) is blockage of an immune checkpoint inhibitor that targets the programmed death of cell ligand 1 receptors (PD-L1). PD-L1 activation results in negative regulatory signals that induce apoptosis and inhibit tumor antigen-specific T cells allowing immune evasion of the tumor.The aim of this aim is to measure the expression level of PD-L1 on oral tissue samples from DLBCL patients using immunohistochemistry. MATERIALS AND METHODS This current study was performed at the Faculty of Dentistry, Tanta University, Egypt. Ethical approval was conducted from Faculty of Dentistry, Tanta University. Tissue samples were collected from 13 patients diagnosed with oral extranodal DLBCL) nongerminal center B cell like subtype. Both hematoxylin and eosin and immunohistochemical staining (The avidin-biotin-complex procedure) was performed with anti-PD-L1 antibody (clone number: 28-8, Abcam, Cambridge, Massachusetts, United States).Cytoplasmic and/or membranous positive intensity was graded as follows: very mild staining, mild staining, moderate staining, and intense staining using Image J, 1.41a (National Institutes of Health, United States) image analysis software. The mean area fraction of the stained cells was calculated by counting immunostained cells in three fields of each case by two pathologists. Data was entered in SPSS program for analysis. RESULTS PD-L1 was overexpressed on tumor cells of oral extranodal DLBCL than control cells from lesion free areas of oral tissues of the same patient.
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Affiliation(s)
- Rania Hanafi Mahmoud Said
- Department of Oral Pathology, Faculty of Dentistry, Suez Canal University, El Salam District Ismailia Governorate, Egypt.,Department of Oral Pathology in Faculty of Dentistry, Umm Al Qura University, Kingdom of Saudi Arabia
| | - Fatma F Hussein
- Department of Oral Medicine, Oral Diagnosis and Periodontology, Faculty of Dentistry, Minia University, Minya, Menia Governorate, Egypt.,Faculty of Dentistry, Umm Al Qura University, Kingdom of Saudi Arabia
| | - Amal M El-Deeb
- Department of Oral Pathology in Faculty of Dentistry, Umm Al Qura University, Kingdom of Saudi Arabia.,Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta, Gharbia Governorate, Egypt
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10
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Saber MM. Diagnostic Performance of PD-L1 versus PD-1 Expression in Circulating CD20 Cells in Diffuse Large B-Cell Lymphoma. Antibodies (Basel) 2022; 11:antib11010015. [PMID: 35225873 PMCID: PMC8884023 DOI: 10.3390/antib11010015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 11/16/2022] Open
Abstract
This study aimed to investigate PD-L1 and PD-1 expression in circulating CD20+ cells in diffuse larger B-cell lymphoma (DLBCL) and to evaluate the predictive and diagnostic performance of PD-L1 versus PD-1 expression in circulating CD20+ cells in DLBCL. Percentages of CD20+, PD-L1+CD20+, and PD-1+CD20+ cells were measured by flow cytometry in 40 DLBCL blood samples and 19 healthy controls. The DLBCL patient group was subdivided into 20 newly diagnosed patients with no treatment yet and 20 patients that had finished six cycles of CHOP therapy. Percentages of PD-L1+CD20+ and PD-1+CD20+ cells were highly significantly increased in pre-therapy patients in comparison to healthy volunteers (p < 0.001). Meanwhile, a significant decrease in percentages of PD-L1+CD20+ and PD-1+CD20+ was observed in post-CHOP therapy patients in comparison to pre-therapy patients (p < 0.001). PD-L1+CD20+ cells were significantly decreased in post-therapy patients when compared to normal controls (p < 0.001), while not for PD-1+CD20+ cells. A strong significant positive correlation between percentages of PD-L1+CD20+ and PD-1+CD20+ was detected in DLBCL patients (p < 0.001). In the pre-therapy group, high PD-L1+CD20+ and PD-1+CD20+ percentages were correlated with serum LDH levels (p = 0.021, p < 0.001). High percentages of PD-1+CD20+ were found in DLBCL patients with splenomegaly (p = 0.027). The results revealed that patients with advanced tumor stages, poor ECOG performance, and non-GCB DLBCL type had increased percentages of PD-L1+CD20+ and PD-1+CD20+ cells. Moreover, PD-L1+CD20+ % and PD-1+CD20+ % were significantly increased in DLBCL patients with bone marrow involvement or B symptoms. The superiority of PD-L1+CD20+ over PD-1+CD20+ was more profound in DLBCL prediction [AUC: 1.0] and in discriminating newly diagnosed patients [AUC: 1.0]. The findings suggest that increased PD-L1/PD-1 expression in peripheral CD20 cells may serve as a companion diagnostic marker for DLBCL. Moreover, percentages of PD-L1+CD20+ cells have better diagnostic performance with higher sensitivity and specificity than PD-1+CD20+ %.
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Affiliation(s)
- Manal Mohamed Saber
- Clinical Pathology Department, Faculty of Medicine, Minia University, Minia 61519, Egypt
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11
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Asrini R, Ham MF, Asmarinah A, Harahap AS, Hardjolukito ESR. Expression of programmed cell death ligand-1 protein in germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. Mol Clin Oncol 2022; 16:42. [PMID: 35003740 DOI: 10.3892/mco.2021.2474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 11/30/2021] [Indexed: 11/06/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide. However, there is still limited information on the expression of programmed cell death ligand-1 (PD-L1), a type 1 transmembrane protein of immunoglobulin B7/CD28 in the DLBCL subtypes. The present study aimed to identify the expression of PD-L1 in germinal center B-cell-like (GCB) subtype and non-germinal center B-cell-like (non-GCB) subtype of DLBCL. A total of 40 patient samples (formalin-fixed paraffin-embedded tissues) consisting of 20 cases of GCB subtype and 20 cases of non-GCB subtype of DLBCL were examined. The PD-L1 protein expressions were evaluated by using immunohistochemical staining in the tumor cells. The results showed a statistically significant difference (P=0.003) between the expression of PD-L1 in the GCB subtype and the non-GCB subtype of DLBCL. PD-L1 expression in the tumor cells were observed in 13 cases (65%) of non-GCB subtype and in three cases (15%) of the GCB subtype of DLBCL. In conclusion, it was found that the expression of PD-L1 protein in the tumor cells of the non-GCB subtype of DLBCL was significantly higher as compared with the tumor cells of the GCB subtype of DLBCL.
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Affiliation(s)
- Rizka Asrini
- Master Program of Biomedical Science, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Maria Francisca Ham
- Human Cancer Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.,Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo National Central General Hospital, Jakarta 10430, Indonesia
| | - Asmarinah Asmarinah
- Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Agnes Stephanie Harahap
- Human Cancer Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.,Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo National Central General Hospital, Jakarta 10430, Indonesia
| | - Endang S R Hardjolukito
- Human Cancer Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.,Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia/Dr. Cipto Mangunkusumo National Central General Hospital, Jakarta 10430, Indonesia
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12
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Zanelli M, Sanguedolce F, Palicelli A, Zizzo M, Martino G, Caprera C, Fragliasso V, Soriano A, Gozzi F, Cimino L, Masia F, Moretti M, Foroni M, De Marco L, Pellegrini D, De Raeve H, Ricci S, Tamagnini I, Tafuni A, Cavazza A, Merli F, Pileri SA, Ascani S. EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 3). Cancers (Basel) 2021; 13:6021. [PMID: 34885131 PMCID: PMC8656853 DOI: 10.3390/cancers13236021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 11/27/2021] [Accepted: 11/28/2021] [Indexed: 12/28/2022] Open
Abstract
EBV is the first known oncogenic virus involved in the development of several tumors. The majority of the global population are infected with the virus early in life and the virus persists throughout life, in a latent stage, and usually within B lymphocytes. Despite the worldwide diffusion of EBV infection, EBV-associated diseases develop in only in a small subset of individuals often when conditions of immunosuppression disrupt the balance between the infection and host immune system. EBV-driven lymphoid proliferations are either of B-cell or T/NK-cell origin, and range from disorders with an indolent behavior to aggressive lymphomas. In this review, which is divided in three parts, we provide an update of EBV-associated lymphoid disorders developing in the gastrointestinal tract, often representing a challenging diagnostic and therapeutic issue. Our aim is to provide a practical diagnostic approach to clinicians and pathologists who face this complex spectrum of disorders in their daily practice. In this part of the review, the chronic active EBV infection of T-cell and NK-cell type, its systemic form; extranodal NK/T-cell lymphoma, nasal type and post-transplant lymphoproliferative disorders are discussed.
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Affiliation(s)
- Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | | | - Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Giovanni Martino
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| | - Cecilia Caprera
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| | - Valentina Fragliasso
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Alessandra Soriano
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Fabrizio Gozzi
- Ocular Immunology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (F.G.); (L.C.)
| | - Luca Cimino
- Ocular Immunology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (F.G.); (L.C.)
| | - Francesco Masia
- Dipartimento di Medicina, Università degli Studi di Perugia, 05100 Terni, Italy; (F.M.); (M.M.)
| | - Marina Moretti
- Dipartimento di Medicina, Università degli Studi di Perugia, 05100 Terni, Italy; (F.M.); (M.M.)
| | - Moira Foroni
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Loredana De Marco
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - David Pellegrini
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
| | - Hendrik De Raeve
- Pathology, University Hospital Brussels, 1090 Brussels, Belgium;
- Pathology, O.L.V. Hospital Aalst, 9300 Aalst, Belgium
| | - Stefano Ricci
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Ione Tamagnini
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Alessandro Tafuni
- Pathology Unit, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy;
| | - Alberto Cavazza
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (M.F.); (L.D.M.); (S.R.); (I.T.); (A.C.)
| | - Francesco Merli
- Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Stefano A. Pileri
- Haematopathology Division, European Institute of Oncology-IEO IRCCS Milan, 20141 Milan, Italy;
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (D.P.); (S.A.)
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13
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Zanelli M, Sanguedolce F, Palicelli A, Zizzo M, Martino G, Caprera C, Fragliasso V, Soriano A, Valle L, Ricci S, Cavazza A, Merli F, Pileri SA, Ascani S. EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1). Cancers (Basel) 2021; 13:4578. [PMID: 34572803 PMCID: PMC8465149 DOI: 10.3390/cancers13184578] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/02/2021] [Accepted: 09/10/2021] [Indexed: 12/21/2022] Open
Abstract
EBV is the most common persistent virus in humans. The interaction of EBV with B lymphocytes, which are considered the virus reservoir, is at the base of the life-long latent infection. Under circumstances of immunosuppression, the balance between virus and host immune system is altered and hence, EBV-associated lymphoid proliferations may originate. These disorders encompass several entities, ranging from self-limited diseases with indolent behavior to aggressive lymphomas. The virus may infect not only B-cells, but even T- and NK-cells. The occurrence of different types of lymphoid disorders depends on both the type of infected cells and the state of host immunity. EBV-driven lymphoproliferative lesions can rarely occur in the gastrointestinal tract and may be missed even by expert pathologists due to both the uncommon site of presentation and the frequent overlapping morphology and immunophenotypic features shared by different entities. The aim of this review is to provide a comprehensive overview of the current knowledge of EBV-associated lymphoproliferative disorders, arising within the gastrointestinal tract. The review is divided in three parts. In this part, the available data on EBV biology, EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, not otherwise specified and classic Hodgkin lymphoma are discussed.
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Affiliation(s)
- Magda Zanelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (S.R.); (A.C.)
| | | | - Andrea Palicelli
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (S.R.); (A.C.)
| | - Maurizio Zizzo
- Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Giovanni Martino
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (S.A.)
| | - Cecilia Caprera
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (S.A.)
| | - Valentina Fragliasso
- Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Alessandra Soriano
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Gastroenterology Division, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Luca Valle
- Anatomic Pathology, Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Stefano Ricci
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (S.R.); (A.C.)
| | - Alberto Cavazza
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.P.); (S.R.); (A.C.)
| | - Francesco Merli
- Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy;
| | - Stefano A. Pileri
- Haematopathology Division, European Institute of Oncology-IEO IRCCS Milan, 20141 Milan, Italy;
| | - Stefano Ascani
- Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy; (G.M.); (C.C.); (S.A.)
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14
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Usuda D, Izumida T, Terada N, Sangen R, Higashikawa T, Sekiguchi S, Tanaka R, Suzuki M, Hotchi Y, Shimozawa S, Tokunaga S, Osugi I, Katou R, Ito S, Asako S, Takagi Y, Mishima K, Kondo A, Mizuno K, Takami H, Komatsu T, Oba J, Nomura T, Sugita M, Kasamaki Y. Diffuse large B cell lymphoma originating from the maxillary sinus with skin metastases: A case report and review of literature. World J Clin Cases 2021; 9:6886-6899. [PMID: 34447839 PMCID: PMC8362537 DOI: 10.12998/wjcc.v9.i23.6886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/12/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma (ML), accounting for 30%-40% of cases of non-Hodgkin’s lymphoma (NHL) in adults. Primary paranasal sinus lymphoma is a rare presentation of extranodal NHL that accounts for only 0.17% of all lymphomas. ML from the maxillary sinus (MS) is a particularly rare presentation, and is thus often difficult to diagnose. We have reported the first known case of DLBCL originating from the MS with rapidly occurrent multiple skin metastasis.
CASE SUMMARY An 81-year-old Japanese man visited our hospital due to continuous pain for 12 d in the left maxillary nerve area. His medical history included splenectomy due to a traffic injury, an old right cerebral infarction from when he was 74-years-old, hypertension, and type 2 diabetes mellitus. A plain head computed tomography (CT) scan revealed a 3 cm × 3.1 cm × 3 cm sized left MS. On day 25, left diplopia and ptosis occurred, and a follow-up CT on day 31 revealed the growth of the left MS mass. Based on an MS biopsy on day 50, we established a definitive diagnosis of DLBCL, non-germinal center B-cell-like originating from the left MS. The patient was admitted on day 62 due to rapid deterioration of his condition, and a plain CT scan revealed the further growth of the left MS mass, as well as multiple systemic metastasis, including of the skin. A skin biopsy on day 70 was found to be the same as that of the left MS mass. We notified the patient and his family of the disease, and they opted for palliative care, considering on his condition and age. The patient died on day 80.
CONCLUSION This case suggests the need for careful, detailed examination, and for careful follow-up, when encountering patients presenting with a mass.
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Affiliation(s)
- Daisuke Usuda
- Department of General Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama-ken, Japan
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Toshihide Izumida
- Department of General Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama-ken, Japan
| | - Nao Terada
- Department of General Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama-ken, Japan
| | - Ryusho Sangen
- Department of General Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama-ken, Japan
| | - Toshihiro Higashikawa
- Department of Geriatric Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama-ken, Japan
| | - Sayumi Sekiguchi
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Risa Tanaka
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Makoto Suzuki
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Yuta Hotchi
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Shintaro Shimozawa
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Shungo Tokunaga
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Ippei Osugi
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Risa Katou
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Sakurako Ito
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Suguru Asako
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Yoshie Takagi
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Kentaro Mishima
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Akihiko Kondo
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Keiko Mizuno
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Hiroki Takami
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Takayuki Komatsu
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Jiro Oba
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Tomohisa Nomura
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Manabu Sugita
- Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Nerima-ku 177-0035, Tokyo-to, Japan
| | - Yuji Kasamaki
- Department of General Medicine, Kanazawa Medical University Himi Municipal Hospital, Himi-shi 935-8531, Toyama-ken, Japan
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15
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Ishikawa E, Satou A, Nakamura M, Nakamura S, Fujishiro M. Epstein-Barr Virus Positive B-Cell Lymphoproliferative Disorder of the Gastrointestinal Tract. Cancers (Basel) 2021; 13:3815. [PMID: 34359715 PMCID: PMC8345108 DOI: 10.3390/cancers13153815] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022] Open
Abstract
Epstein-Barr virus positive B-cell lymphoproliferative disorder (EBV+ B-LPD) encompasses a broad clinicopathological spectrum and distinct clinical behavior that relatively favors the gastrointestinal (GI) tract. In this review, we provide an update on the clinicopathological features and biological behavior of EBV-positive mucocutaneous ulcer (EBVMCU) and primary EBV+ diffuse large B-cell lymphoma (DLBCL) of the GI tract. EBVMCU is a newly recognized entity but well known as an indolent and self-limited EBV+ B-LPD occurring in various immunodeficiencies. In contrast, EBV+ DLBCL constitutes the largest group of EBV+ B-LPDs and is regarded as an aggressive neoplasm. These two distinct diseases have historically been distinguished in the reappraisal of age-related EBV-associated B-LPDs but are challenging in routine practice regarding their differential diagnostic and therapeutic approaches. An increasing number of reports indicate that they are epidemiologically prevalent beyond western and eastern countries, but their comprehensive analysis is still limited. We also describe the PD-L1 positivity of tumorous large cells and non-malignant immune cells, which is relevant for the prognostic delineation among patients with primary DLBCL of the GI tract with and without EBV on tumor cells.
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Affiliation(s)
- Eri Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (M.N.); (M.F.)
| | - Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan;
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (M.N.); (M.F.)
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya 466-8550, Japan;
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan; (M.N.); (M.F.)
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16
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Epstein-Barr virus recruits PDL1-positive cells at the microenvironment in pediatric Hodgkin lymphoma. Cancer Immunol Immunother 2021; 70:1519-1526. [PMID: 33184699 DOI: 10.1007/s00262-020-02787-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Classic Hodgkin lymphoma (cHL) is a lymphoid malignancy in which the microenvironment, where the neoplastic cells are immersed, contributes to the lymphomagenesis process. Epstein-Barr virus (EBV) presence also influences cHL microenvironment composition and contributes to pathogenesis. An increase in PDL1 expression in tumor cells and at the microenvironment was demonstrated in adult cHL. Therefore, our aim was to assess PD1/PDL1 pathway and EBV influence on this pathway in pediatric cHL, given that in Argentina, our group proved a higher incidence of EBV-associated pediatric lymphoma in children. METHODS For that purpose, EBV presence was assessed by in situ hybridization, whereas PD1 and PDL1 expressions were studied by immunohistochemistry. PDL1 genetic alterations were analyzed by FISH, and survival was evaluated for PD1 and PDL1 expressions. RESULTS EBV presence demonstrated no influence neither on PD1 expression at the microenvironment nor on PDL1 expression at HRS tumor cells. Unexpectedly, only 38% pediatric cHL displayed PDL1 genetic alterations by FISH, and no difference was observed regarding EBV presence. However, in EBV-related cHL cases, a higher number of PDL1 + cells were detected at the microenvironment. CONCLUSION Even though a high cytotoxic environment was previously described in EBV-related pediatric cHL, it might be counterbalanced by an immunoregulatory micro-environmental PDL1 + niche. This regulation may render a cytotoxic milieu that unsuccessfully try to eliminate EBV + Hodgkin Reed Sternberg tumor cells in pediatric patients.
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17
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Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade. Blood Adv 2021; 5:1816-1829. [PMID: 33787861 DOI: 10.1182/bloodadvances.2020003080] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 02/16/2021] [Indexed: 12/22/2022] Open
Abstract
In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell-like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.
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18
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Papageorgiou SG, Thomopoulos TP, Katagas I, Bouchla A, Pappa V. Prognostic molecular biomarkers in diffuse large B-cell lymphoma in the rituximab era and their therapeutic implications. Ther Adv Hematol 2021; 12:20406207211013987. [PMID: 34104369 PMCID: PMC8150462 DOI: 10.1177/20406207211013987] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) represents a group of tumors characterized by substantial heterogeneity in terms of their pathological and biological features, a causal factor of their varied clinical outcome. This variation has persisted despite the implementation of rituximab in treatment regimens over the last 20 years. In this context, prognostic biomarkers are of great importance in order to identify high-risk patients that might benefit from treatment intensification or the introduction of novel therapeutic agents. Herein, we review current knowledge on specific immunohistochemical or genetic biomarkers that might be useful in clinical practice. Gene-expression profiling is a tool of special consideration in this effort, as it has enriched our understanding of DLBCL biology and has allowed for the classification of DLBCL by cell-of-origin as well as by more elaborate molecular signatures based on distinct gene-expression profiles. These subgroups might outperform individual biomarkers in terms of prognostication; however, their use in clinical practice is still limited. Moreover, the underappreciated role of the tumor microenvironment in DLBCL prognosis is discussed in terms of prognostic gene-expression signatures, as well as in terms of individual biomarkers of prognostic significance. Finally, the efficacy of novel therapeutic agents for the treatment of DLBCL patients are discussed and an evidence-based therapeutic approach by specific genetic subgroup is suggested.
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Affiliation(s)
- Sotirios G. Papageorgiou
- Second Department of Internal Medicine and Research Unit, University General Hospital ‘Attikon’, 1 Rimini Street, Haidari, Athens 12462, Greece
| | - Thomas P. Thomopoulos
- Second Department of Internal Medicine and Research Unit, Hematology Unit, University General Hospital, ‘Attikon’, Haidari, Athens, Greece
| | - Ioannis Katagas
- Second Department of Internal Medicine and Research Unit, Hematology Unit, University General Hospital, ‘Attikon’, Haidari, Athens, Greece
| | - Anthi Bouchla
- Second Department of Internal Medicine and Research Unit, Hematology Unit, University General Hospital, ‘Attikon’, Haidari, Athens, Greece
| | - Vassiliki Pappa
- Second Department of Internal Medicine and Research Unit, Hematology Unit, University General Hospital, ‘Attikon’, Haidari, Athens, Greece
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19
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Integrative Statistics, Machine Learning and Artificial Intelligence Neural Network Analysis Correlated CSF1R with the Prognosis of Diffuse Large B-Cell Lymphoma. HEMATO 2021. [DOI: 10.3390/hemato2020011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumor-associated macrophages (TAMs) of the immune microenvironment play an important role in the Diffuse Large B-cell Lymphoma (DLBCL) pathogenesis. This research aimed to characterize the expression of macrophage colony-stimulating factor 1 receptor (CSF1R) at the gene and protein level in correlation with survival. First, the immunohistochemical expression of CSF1R was analyzed in a series of 198 cases from Tokai University Hospital and two patterns of histological expression were found, a TAMs, and a diffuse B-lymphocytes pattern. The clinicopathological correlations showed that the CSF1R + TAMs pattern associated with a poor progression-free survival of the patients, disease progression, higher MYC proto-oncogene expression, lower MDM2 expression, BCL2 translocation, and a MYD88 L265P mutation. Conversely, a diffuse CSF1R + B-cells pattern was associated with a favorable progression-free survival. Second, the histological expression of CSF1R was also correlated with 10 CSF1R-related markers including CSF1, STAT3, NFKB1, Ki67, MYC, PD-L1, TNFAIP8, IKAROS, CD163, and CD68. CSF1R moderately correlated with STAT3, TNFAIP8, CD68, and CD163 in the cases with the CSF1R + TAMs pattern. In addition, machine learning modeling predicted the CSF1R immunohistochemical expression with high accuracy using regression, generalized linear, an artificial intelligence neural network (multilayer perceptron), and support vector machine (SVM) analyses. Finally, a multilayer perceptron analysis predicted the genes associated with the CSF1R gene expression using the GEO GSE10846 DLBCL series of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP), with correlation to the whole set of 20,683 genes as well as with an immuno-oncology cancer panel of 1790 genes. In addition, CSF1R positively correlated with SIRPA and inversely with CD47. In conclusion, the CSF1R histological pattern correlated with the progression-free survival of the patients of the Tokai series, and predictive analytics is a feasible strategy in DLBCL.
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20
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The Incidence of Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:cancers13081785. [PMID: 33917961 PMCID: PMC8068359 DOI: 10.3390/cancers13081785] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/03/2021] [Accepted: 04/05/2021] [Indexed: 11/23/2022] Open
Abstract
Simple Summary The worldwide prevalence of Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) is undetermined. There is no clearly defined cut-off for EBV-encoded RNA (EBER) positivity in tumor cells by in situ hybridization. A lack of common criteria for positive expression of EBER has been raised as a limitation for interpreting and understanding the geographic and ethnic disparity of prevalence of EBV+ DLBCL. We conducted a systematic literature review and meta-analysis to establish the proportions of EBV+ DLBCL patients. Results showed that the pooled proportion of EBER positivity was 7.9% in patients with de novo DLBCL. The prevalence of EBV+ DLBCL was significantly higher in Asia and South America compared with Western countries. A tendency for lower pooled proportions was observed in studies using a higher cut-off for EBER positivity. The patients’ age did not significantly affect the prevalence. These findings may improve our current knowledge of the EBV+ DLBCL. Abstract The worldwide prevalence of Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) is undetermined. There is no clearly defined cut-off for EBV-encoded RNA (EBER) positivity in tumor cells by in-situ hybridization. The purpose of this study was to establish the proportions of EBV+ DLBCL patients and influence of the different cut-offs for EBER positivity, geographical location, and age on the prevalence of EBV+ DLBCL. PubMed and EMBASE were searched for studies published up to May 28, 2020 that reported proportions of EBER positivity in immunocompetent and de novo DLBCL patients. The pooled proportions were computed by an inverse variance method for calculating the weights and the DerSimonian–Laird method. Multiple subgroup analyses were conducted to explore any heterogeneity. Thirty-one studies (8249 patients) were included. The pooled proportion of EBV+ DLBCL was 7.9% (95% CI, 6.2–10.0%) with significant heterogeneity among studies (p < 0.001). The prevalence of EBV+ DLBCL was significantly higher in Asia and South America compared with Western countries (p < 0.01). The cut-offs for EBER positivity (10%, 20%, 50%) and patients’ age (≥50 years vs. <50 years) did not significantly affect the prevalence (p ≥ 0.10). EBV+ DLBCL is rare with a pooled proportion of 7.9% in patients with DLBCL and the geographic heterogeneity was confirmed.
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21
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Rong Q, Gao Y, Cai Q, Wang X, Bai B, Ping L, He H, Rao H, Zhang Y, Li Z, Cai Q, Jiang W, Huang H. High IL-6 expression in the tumor microenvironment is associated with poor prognosis of patients with extranodal natural / killer T-cell lymphoma (ENKTL). Expert Rev Anticancer Ther 2021; 21:121-127. [PMID: 33397158 DOI: 10.1080/14737140.2021.1853531] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Objectives: Extranodal natural/killer T-cell lymphoma (ENKTL) is a rare subtype of T cell non-Hodgkin's lymphoma. Current clinical prognostic models for ENKTL still have their limitations. Validated prognostic models for ENKTL have not yet been established. Methods: Tumor microenvironment IL-6 was measured by immunohistochemistry in 78 ENKTL patients. Results: Patients with negative IL-6 expression in the tumor microenvironment have a longer PFS (56.0 months vs. 25.6 months, p < 0.001) and OS (96.0 months vs. 43.3 months, p < 0.001). In the multivariate analysis, tumor microenvironment IL-6 [p = 0.048, HR = 1.76(1.00-3.08)] and extranodal involvement [p = 0.001, HR = 2.69(1.50-4.82)] were independent prognostic factors for PFS. Tumor microenvironment IL-6 [p = 0.033, HR = 2.69 (1.08-6.67)], Ann Arbor stage [p = 0.002, HR = 2.77 (1.47-5.23)] and B symptom [p = 0.027, HR = 2.02 (1.08-3.78)] were independent prognostic factors for OS. Expert opinion: A high IL-6 expression was related to poor survival, which may be a valuable biomarker for prognostic evaluation at baseline in ENKTL. These results showed that anti-IL-6R may be a potential targeted therapy for the treatment of advanced or relapsed ENKTL.
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Affiliation(s)
- Qixiang Rong
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Yan Gao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Qichun Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Xiaoxiao Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Bing Bai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Liqin Ping
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Haixia He
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Huilan Rao
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, China
| | - Yujing Zhang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Zhiming Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Qingqing Cai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Wenqi Jiang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
| | - Huiqiang Huang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, Guangdong, China
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22
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Hodkinson BP, Schaffer M, Brody JD, Jurczak W, Carpio C, Ben-Yehuda D, Avivi I, Forslund A, Özcan M, Alvarez J, Ceulemans R, Fourneau N, Younes A, Balasubramanian S. Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation. Transl Oncol 2020; 14:100977. [PMID: 33395752 PMCID: PMC7723809 DOI: 10.1016/j.tranon.2020.100977] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/11/2020] [Accepted: 11/25/2020] [Indexed: 12/30/2022] Open
Abstract
Biomarkers of response to ibrutinib + nivolumab were analyzed in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma and Richter transformation. DLBCL patients with elevated PD-L1 by immunohistochemistry tended to have better response and survival. Whole exome sequencing identified gene mutations in alternate B-cell receptor pathways linked to response in DLBCL. Enriched pathways by gene expression profiling were related to immune activation in responders and proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses on genetically defined subsets of patients most likely to benefit from ibrutinib + nivolumab. We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell–like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.
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Affiliation(s)
- Brendan P Hodkinson
- Oncology Translational Research, Janssen Research & Development, Spring House, PA 19477, United States
| | - Michael Schaffer
- Oncology Translational Research, Janssen Research & Development, Spring House, PA 19477, United States
| | - Joshua D Brody
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Wojciech Jurczak
- Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, 31-115, Poland
| | - Cecilia Carpio
- Department of Hematology, University Hospital Vall d'Hebron, Department of Medicine. Universitat Autònoma de Barcelona (UAB), Vall d'Hebron Institut of Oncology (VHIO), Barcelona, Spain
| | - Dina Ben-Yehuda
- Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Irit Avivi
- Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv 6997801, Israel
| | - Ann Forslund
- Oncology Biomarkers, Bristol-Myers Squibb, Lawrenceville, NJ 08543, United States
| | - Muhit Özcan
- Department of Hematology, Ankara University School of Medicine, Ankara 06100, Turkey
| | - John Alvarez
- Oncology Translational Research, Janssen Research & Development, Spring House, PA 19477, United States
| | - Rob Ceulemans
- Translational Medicine, Janssen Research & Development, Beerse 2340, Belgium
| | - Nele Fourneau
- Translational Medicine, Janssen Research & Development, Beerse 2340, Belgium
| | - Anas Younes
- Lymphoma Department, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
| | - Sriram Balasubramanian
- Oncology Translational Research, Janssen Research & Development, Spring House, PA 19477, United States.
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23
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de Jonge AV, Mutis T, Roemer MGM, Scheijen B, Chamuleau MED. Impact of MYC on Anti-Tumor Immune Responses in Aggressive B Cell Non-Hodgkin Lymphomas: Consequences for Cancer Immunotherapy. Cancers (Basel) 2020; 12:cancers12103052. [PMID: 33092116 PMCID: PMC7589056 DOI: 10.3390/cancers12103052] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/12/2020] [Accepted: 10/16/2020] [Indexed: 02/08/2023] Open
Abstract
Simple Summary The human immune system has several mechanisms to attack and eliminate lymphomas. However, the MYC oncogene is thought to facilitate escape from this anti-tumor immune response. Since patients with MYC overexpressing lymphomas face a significant dismal prognosis after treatment with standard immunochemotherapy, understanding the role of MYC in regulating the anti-tumor immune response is highly relevant. In this review, we describe the mechanisms by which MYC attenuates the anti-tumor immune responses in B cell non-Hodgkin lymphomas. We aim to implement this knowledge in the deployment of novel immunotherapeutic approaches. Therefore, we also provide a comprehensive overview of current immunotherapeutic options and we discuss potential future treatment strategies for MYC overexpressing lymphomas. Abstract Patients with MYC overexpressing high grade B cell lymphoma (HGBL) face significant dismal prognosis after treatment with standard immunochemotherapy regimens. Recent preclinical studies indicate that MYC not only contributes to tumorigenesis by its effects on cell proliferation and differentiation, but also plays an important role in promoting escape from anti-tumor immune responses. This is of specific interest, since reversing tumor immune inhibition with immunotherapy has shown promising results in the treatment of both solid tumors and hematological malignancies. In this review, we outline the current understanding of impaired immune responses in B cell lymphoid malignancies with MYC overexpression, with a particular emphasis on diffuse large B cell lymphoma. We also discuss clinical consequences of MYC overexpression in the treatment of HGBL with novel immunotherapeutic agents and potential future treatment strategies.
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Affiliation(s)
- A. Vera de Jonge
- Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081HV Amsterdam, The Netherlands; (T.M.); (M.E.D.C.)
- Correspondence:
| | - Tuna Mutis
- Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081HV Amsterdam, The Netherlands; (T.M.); (M.E.D.C.)
| | - Margaretha G. M. Roemer
- Department of Pathology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081HV Amsterdam, The Netherlands;
| | - Blanca Scheijen
- Department of Pathology, Radboud UMC, Radboud Institute for Molecular Life Sciences, 6525GA Nijmegen, The Netherlands;
| | - Martine E. D. Chamuleau
- Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, 1081HV Amsterdam, The Netherlands; (T.M.); (M.E.D.C.)
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24
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Landsburg DJ, Koike A, Nasta SD, Svoboda J, Schuster SJ, Wasik MA, Caponetti GC. Patterns of immune checkpoint protein expression in MYC-overexpressing aggressive B-cell non-Hodgkin lymphomas. Cancer Immunol Immunother 2020; 70:869-874. [PMID: 32857184 DOI: 10.1007/s00262-020-02708-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 08/19/2020] [Indexed: 12/16/2022]
Abstract
Given the poor prognosis of MYC-overexpressing diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma/high grade B cell lymphoma (BCLU/HGBL), and preclinical data suggesting that MYC may regulate the antitumor immune response, we sought to characterize expression of immune checkpoint proteins on tumor tissue from patients diagnosed with these lymphomas. Immunohistochemical staining for immune checkpoint protein expression was applied to 56 cases of MYC-overexpressing DLBCL and BCLU/HGBL, 35 of which also harbored MYC rearrangement (MYC-R). Analysis revealed both frequent overexpression of immune checkpoint proteins as well as differences in overexpression patterns based upon MYC-R status, with MYC-R cases more likely to overexpress PD-L1 and PD-1 in the tumor microenvironment (50 vs. 15%, p = 0.02 and 32 vs. 5%, p = 0.02, respectively) but less likely to overexpress CTLA-4 and CD80 on tumor cells (34 vs. 71%, p = 0.01 and 34 vs. 81%, p = 0.001, respectively), as compared to cases without MYC-R. These data may suggest a biologic rationale for investigation of the effect of checkpoint inhibitor therapies in these subgroups of MYC-overexpressing DLBCL and BCLU/HGBL.
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Affiliation(s)
| | - Alexa Koike
- University of Pennsylvania, Philadelphia, PA, USA
| | | | | | | | - Mariusz A Wasik
- Fox Chase Cancer Center and University of Pennsylvania, Philadelphia, USA
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25
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Krittikarux S, Wudhikarn K, Tangnuntachai N, Assanasen T, Sukswai N, Asawapanumas T, Chanswangphuwana C. The influence of programmed cell death ligand 2 (PD-L2) expression on survival outcome and tumor microenvironment in diffuse large B cell lymphoma. Leuk Lymphoma 2020; 61:3395-3403. [PMID: 32820659 DOI: 10.1080/10428194.2020.1808209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The frequency and significance of programmed cell death ligand (PD-L) 2 expression in diffuse large B cell lymphoma (DLBCL) remain undefined. We described the expression pattern of PD-L/PD-1 in 88 DLBCL patients using immunohistochemistry. The association between PD-L expression and clinical characteristics/outcomes were analyzed. PD-L1 and PD-L2 were expressed in 14.8% and 68.2% of DLBCL patients with median positivity on tumor cells of 100% and 90%, respectively. PD-1 on tumor-infiltrating lymphocytes (TILs) was expressed in 12.5% of patients. Interestingly, 45.5% of patients had PD-L2 expressing TILs which were significantly associated with bulky disease (p = .046) and elevated lactate dehydrogenase (p = .048). PD-L1 and/or PD-L2 expression on lymphoma cells was associated with inferior progression-free survival (Hazard ratio [HR] 2.20; 95% Confidence Interval [CI] 1.004-4.84, p = .049) and overall survival (HR 2.27; 95%CI 1.03-4.98, p = .042), using multivariate analysis. In summary, PD-L2 expression on DLBCL is common and, together with PD-L1, were related to poor outcomes.
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Affiliation(s)
- San Krittikarux
- Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand
| | - Kitsada Wudhikarn
- Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand
| | - Nichthida Tangnuntachai
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Thamathorn Assanasen
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Narittee Sukswai
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Thiti Asawapanumas
- Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand
| | - Chantiya Chanswangphuwana
- Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand
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26
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Takahara T, Satou A, Ishikawa E, Kohno K, Kato S, Suzuki Y, Takahashi E, Ohashi A, Asano N, Tsuzuki T, Nakamura S. Clinicopathological analysis of neoplastic PD-L1-positive EBV + diffuse large B cell lymphoma, not otherwise specified, in a Japanese cohort. Virchows Arch 2020; 478:541-552. [PMID: 32803453 DOI: 10.1007/s00428-020-02901-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/09/2020] [Accepted: 08/06/2020] [Indexed: 12/15/2022]
Abstract
The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in the pathogenesis of Epstein-Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). Here, we describe PD-L1 expression by EBV+ DLBCL, NOS in order to evaluate its possible contribution to the pathogenesis of this tumor. The study included 57 cases of EBV+ DLBCL, NOS. The median patient age was 69 years and 95% (n = 54) were aged > 45. Extranodal lesions were present in 39 (69%) at initial diagnosis. PD-L1 expression (mAb SP142-positive staining) was present in more than 5% of tumor cells in only six cases (11%), in clear contrast to the 77% reported in cases aged under 45 years. Among the PD-L1+ cases, three were nodal lesions. All six PD-L1+ cases progressed in the 3 years after diagnosis and four of the six patients died of the disease within 2 years. PD-L1+ cases had significantly shorter PFS (P = 0.002) and relatively short OS (P = 0.26), compared with PD-L1- cases. EBV+ DLBCL, NOS in the elderly infrequently expressed PD-L1 and had poor prognosis. PD-L1 expression in EBV+ DLBCL, NOS of the elderly sheds light on the pathogenetic role of immune senescence.
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Affiliation(s)
- Taishi Takahara
- Department of Surgical Pathology, Aichi Medical University Hospital, 1-1, Yazakokarimata, Nagakute, 480-1195, Japan.
| | - Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, 1-1, Yazakokarimata, Nagakute, 480-1195, Japan
| | - Eri Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kei Kohno
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Seiichi Kato
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yuka Suzuki
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Emiko Takahashi
- Department of Surgical Pathology, Aichi Medical University Hospital, 1-1, Yazakokarimata, Nagakute, 480-1195, Japan
| | - Akiko Ohashi
- Department of Surgical Pathology, Aichi Medical University Hospital, 1-1, Yazakokarimata, Nagakute, 480-1195, Japan
| | - Naoko Asano
- Department of Clinical Laboratory, Nagano Prefectural Suzaka Hospital, Nagano, Japan
| | - Toyonori Tsuzuki
- Department of Surgical Pathology, Aichi Medical University Hospital, 1-1, Yazakokarimata, Nagakute, 480-1195, Japan
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
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Eladl E, Tremblay-LeMay R, Rastgoo N, Musani R, Chen W, Liu A, Chang H. Role of CD47 in Hematological Malignancies. J Hematol Oncol 2020; 13:96. [PMID: 32677994 PMCID: PMC7364564 DOI: 10.1186/s13045-020-00930-1] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent "don't eat me" signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.
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Affiliation(s)
- Entsar Eladl
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, 11th floor, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada
| | - Rosemarie Tremblay-LeMay
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, 11th floor, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada
| | - Nasrin Rastgoo
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, 11th floor, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada
| | - Rumina Musani
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, 11th floor, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada
| | - Wenming Chen
- Department of Hematology, Beijing Chaoyang Hospital, Capital University, Beijing, China
| | - Aijun Liu
- Department of Hematology, Beijing Chaoyang Hospital, Capital University, Beijing, China.
| | - Hong Chang
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, University of Toronto, 11th floor, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada.
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Hajifathali A, Parkhideh S, Kazemi MH, Chegeni R, Roshandel E, Gholizadeh M. Immune checkpoints in hematologic malignancies: What made the immune cells and clinicians exhausted! J Cell Physiol 2020; 235:9080-9097. [DOI: 10.1002/jcp.29769] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/27/2020] [Accepted: 04/27/2020] [Indexed: 12/22/2022]
Affiliation(s)
- Abbas Hajifathali
- Hematopoietic Stem Cell Research Center Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Sayeh Parkhideh
- Hematopoietic Stem Cell Research Center Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Mohammad H. Kazemi
- Hematopoietic Stem Cell Research Center Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Rouzbeh Chegeni
- The Michener Institute of Education at University Health Network Toronto Canada
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Majid Gholizadeh
- Hematopoietic Stem Cell Research Center Shahid Beheshti University of Medical Sciences Tehran Iran
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29
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Beltran BE, Castro D, Paredes S, Miranda RN, Castillo JJ. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2020 update on diagnosis, risk-stratification and management. Am J Hematol 2020; 95:435-445. [PMID: 32072672 DOI: 10.1002/ajh.25760] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 12/13/2022]
Abstract
DISEASE OVERVIEW Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 WHO classification of lymphoid neoplasms. EBV+ DLBCL, NOS, is an aggressive B-cell lymphoma associated with chronic EBV infection, and a poor prognosis with standard chemotherapeutic approaches. DIAGNOSIS The diagnosis is made through a careful pathological evaluation. Detection of EBV-encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation and primary effusion lymphoma (PEL), among others. RISK-STRATIFICATION The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. MANAGEMENT Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.
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Affiliation(s)
- Brady E. Beltran
- Department of Oncology and Radiotherapy Hospital Nacional Edgardo Rebagliati Martins Lima Peru
- Centro de Investigación de Medicina de Precision, Universidad San Martin de Porres Lima Peru
| | - Denisse Castro
- Department of Oncology and Radiotherapy Hospital Nacional Edgardo Rebagliati Martins Lima Peru
- Centro de Investigación de Medicina de Precision, Universidad San Martin de Porres Lima Peru
| | - Sally Paredes
- Department of Oncology and Radiotherapy Hospital Nacional Edgardo Rebagliati Martins Lima Peru
- Centro de Investigación de Medicina de Precision, Universidad San Martin de Porres Lima Peru
| | - Roberto N. Miranda
- Department of Hematopathology The University of Texas MD Anderson Cancer Center Houston Texas USA
| | - Jorge J. Castillo
- Division of Hematologic Malignancies Dana‐Farber Cancer Institute, Harvard Medical School Boston Massachusetts USA
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30
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Zhou QH, Han H, Lu JB, Liu TY, Huang KB, Deng CZ, Li ZS, Chen JP, Yao K, Qin ZK, Liu ZW, Li YH, Guo SJ, Ye YL, Zhou FJ, Liu RY. Up-regulation of indoleamine 2,3-dioxygenase 1 (IDO1) expression and catalytic activity is associated with immunosuppression and poor prognosis in penile squamous cell carcinoma patients. Cancer Commun (Lond) 2020; 40:3-15. [PMID: 32125093 PMCID: PMC7163927 DOI: 10.1002/cac2.12001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022] Open
Abstract
Background Indoleamine 2,3‐dioxygenase 1 (IDO1) and tryptophan (Trp) catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penile squamous cell carcinoma (PSCC) and explored their clinical significance. Methods IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn) were examined in 114 PSCC patients by immunohistonchemistry and solid‐phase extraction‐liquid chromatography‐tandem mass spectrometry. The survival was analyzed using Kaplan‐Meier method and the log‐rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were defined by principal component analysis. The correlativity was assessed by Pearson's correlation analysis. Results The expression level of IDO1 in PSCC cells was positively correlated with serum Kyn concentration and Kyn/Trp radio (KTR; both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 up‐regulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008 and 0.032, respectively). High expression level of IDO1 in cancer cells and serum KTR were associated with short disease‐specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926; 95% confidence interval [CI], 2.458‐19.068; P < 0.001) and pathologic grade (HR, 2.194; 95% CI, 1.021‐4.529; P = 0.038), only serum KTR (HR, 2.780; 95% CI, 1.066‐7.215; P = 0.036) was an independent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon‐γ (IFNγ, P < 0.001) and immunosuppressive markers (programmed cell death protein 1, cytotoxic T‐lymphocyte‐associated protein 4 and programmed death‐ligand 1 and 2; all P < 0.05), and the infiltration of immune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells; all P < 0.001) in PSCC tissues. Furthermore, the expression of IDO1 was induced by IFNγ in a dose‐dependent manner in PSCC cells. Conclusions IFNγ‐induced IDO1 plays a crucial role in immunoediting and immunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1 catabolic activity, can be utilized as an independent prognostic factor for PSCC.
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Affiliation(s)
- Qiang-Hua Zhou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China
| | - Hui Han
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Jia-Bin Lu
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Ting-Yu Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Kang-Bo Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Chuang-Zhong Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China
| | - Zai-Shang Li
- Department of Urology, Shenzhen People's Hospital, Jinan University, Shenzhen, Guangdong, 518021, P. R. China
| | - Jie-Ping Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China
| | - Kai Yao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Zi-Ke Qin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Zhuo-Wei Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Yong-Hong Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Sheng-Jie Guo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Yun-Lin Ye
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Fang-Jian Zhou
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China.,Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - Ran-Yi Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, P. R. China
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31
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Zeng Q, Liu Z, Liu T. Prognostic value and clinicopathological characteristics of PD-L1 overexpression in non-Hodgkin lymphoma: a meta-analysis. BMC Cancer 2020; 20:59. [PMID: 31992262 PMCID: PMC6986088 DOI: 10.1186/s12885-020-6550-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/16/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Programmed cell death ligand 1 (PD-L1) has already been detected in various carcinomas. In non-Hodgkin lymphoma (NHL), however, the prognostic value of PD-L1 overexpression remains unclear. METHODS A meta-analysis of 2321 NHL patients from 12 studies was performed. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the correlation between PD-L1 overexpression and prognosis of NHL, and odds ratios (ORs) with 95% CIs were used to assess the association of PD-L1 overexpression with clinicopathological factors. RESULTS The results showed that no significant difference between PD-L1 positive and negative groups was detected in NHL (HR: 1.40, 95% CI: 0.90-2.19; P = 0.137). Nevertheless, the results indicated that PD-L1 overexpression was associated with poor prognosis in the subtype of diffuse large B cell lymphoma (DLBCL) (HR: 1.70, 95% CI: 1.05-2.74; P = 0.031). We also performed subgroup analyses and meta-regression. The pooled OR showed that PD-L1 overexpression was associated with B symptoms, higher international prognostic index (IPI) score (3, 4, and 5 points) and Ann Arbor Stages III and IV. CONCLUSIONS The meta-analysis demonstrated that PD-L1 expression was not associated with prognosis of NHL but was associated with prognosis of DLBCL.
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Affiliation(s)
- Qiang Zeng
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhigang Liu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ting Liu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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32
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Tumor Microenvironment in Diffuse Large B-Cell Lymphoma: Role and Prognosis. Anal Cell Pathol (Amst) 2019; 2019:8586354. [PMID: 31934533 PMCID: PMC6942707 DOI: 10.1155/2019/8586354] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 11/06/2019] [Indexed: 12/23/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) represents 30-40% of all non-Hodgkin lymphomas (NHL) and is a disease with an aggressive behavior. Because about one-third of DLBCL patients will be refractory or resistant to standard therapy, several studies focused on identification of new individual prognostic and risk stratification biomarkers and new potential therapeutic targets. In contrast to other types of cancers like carcinomas, where tumor microenvironment was widely investigated, its role in DLBCL pathogenesis and patient survival is still poorly understood, although few studies had promising results. The composition of TME and its interaction with neoplastic cells may explain the role of several genes (beta2-microglobulin gene, CD58 gene), receptor-like programmed cell death-1 (PD-1) and its ligand (PD-L1), or other cell components (Treg) in tumor evasion of immune surveillance, resulting in tumor progression. Also, it was found that “gene expression profile” of the microenvironmental cells, the phenotype of tumor-associated macrophages (TAM), the expression of matricellular proteins like SPARC and fibronectin, the overexpression of several types of matrix metalloproteinases (MMPs) like MMP-2 and MMP-9, or the tissue inhibitors of matrix metalloproteinases (TIMPs) may lead to a favorable or adverse outcome. With this review, we try to highlight the influence of microenvironment components over lymphoid clone progression and their prognostic impact in DLBCL patients.
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Lu TX, Wu S, Zhou XY, Zhang Y, Hong TT, Cai DY, Hua HY, Qi XW, Wu XH. CD5 +MYC + predicts worse prognosis in diffuse large B-cell lymphoma. Exp Mol Pathol 2019; 112:104326. [PMID: 31706988 DOI: 10.1016/j.yexmp.2019.104326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 10/19/2019] [Accepted: 10/27/2019] [Indexed: 11/19/2022]
Abstract
The dual expression of CD5 and MYC protein (DECM) on B-lymphocytes may arise at a specific stage of de novo diffuse large B-cell lymphoma (DLBCL). This study retrospectively reviewed 210 patients with de novo DLBCL at the Affiliated Hospital of Jiangnan University between 2006 and 2017. DECM was significantly correlated with a worse prognosis than that in either the CD5+ or MYC+ or CD5-MYC- patients. Furthermore, patients with DECM showed a similar outcome to MYC+BCL2+ lymphoma patients who have extremely poor survival rates. Multivariate analysis demonstrated that DECM was a significant independent predictor for overall survival (P < .0001) and progression-free survival (P < .0001) in DLBCL. DLBCL patients with DECM showed significantly inferior clinical outcomes compared to the CD5+, MYC+ or CD5-MYC- patients. Combinational therapeutic modalities might be a candidate approach to improve the prognosis of these patients.
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Affiliation(s)
- Ting-Xun Lu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Shuang Wu
- Department of Hematology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Xin-Yi Zhou
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Ying Zhang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Ting-Ting Hong
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Dong-Yan Cai
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Hai-Ying Hua
- Department of Hematology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Xiao-Wei Qi
- Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China
| | - Xiao-Hong Wu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214000, Jiangsu, PR China.
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Wang H, Wu X, Zhang X, Yang X, Long Y, Feng Y, Wang F. Prevalence of NRAS Mutation, PD-L1 Expression and Amplification, and Overall Survival Analysis in 36 Primary Vaginal Melanomas. Oncologist 2019; 25:e291-e301. [PMID: 32043781 PMCID: PMC7011659 DOI: 10.1634/theoncologist.2019-0148] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 08/21/2019] [Indexed: 12/22/2022] Open
Abstract
Background Primary vaginal melanomas are uncommon and aggressive tumors with poor prognosis, and the development of new targeted therapies is essential. This study aimed to identify the molecular markers occurring in these patients and potentially improve treatment strategies. Materials and Methods The clinicopathological characteristics of 36 patients with primary vaginal melanomas were reviewed. Oncogenic mutations in BRAF, KIT, NRAS, GNAQ and GNA11 and the promoter region of telomerase reverse transcriptase (TERT) were investigated using the Sanger sequencing. The expression and copy number of programmed death‐ligand 1 (PD‐L1) were also assessed. Results Mutations in NRAS, KIT, and TERT promoter were identified in 13.9% (5/36), 2.9% (1/34), and 5.6% (2/36) of the primary vaginal melanomas, respectively. PD‐L1 expression and amplification were observed in 27.8% (10/36) and 5.6% (2/36) of cases, respectively. PD‐L1 positive expression and/or amplification was associated with older patients (p = .008). Patients who had NRAS mutations had a poorer overall survival compared with those with a wild‐type NRAS (33.5 vs. 14.0 months; hazard ratio [HR], 3.09; 95% CI, 1.08–8.83). Strikingly, two patients with/without PD‐L1 expression receiving immune checkpoint inhibitors had a satisfying outcome. Multivariate analysis demonstrated that >10 mitoses per mm2 (HR, 2.96; 95% CI, 1.03–8.51) was an independent prognostic factor. Conclusions NRAS mutations and PD‐L1 expression were most prevalent in our cohort of primary vaginal melanomas and can be potentially considered as therapeutic targets. Implications for Practice This study used the Sanger sequencing, immunohistochemistry, and fluorescence in situ hybridization methods to detect common genetic mutations and PD‐L1 expression and copy number in 36 primary vaginal melanomas. NRAS mutations and PD‐L1 expression were the most prevalent, but KIT and TERT mutations occurred at a lower occurrence in this rare malignancy. Two patients receiving immune checkpoint inhibitors had a satisfying outcome, signifying that the PD‐L1 expression and amplification can be a possible predictive marker of clinical response. This study highlights the possible prospects of biomarkers that can be used for patient selection in clinical trials involving treatments with novel targeted therapies based on these molecular aberrations. Little is known about the molecular characteristics of primary vaginal melanoma. This article reports on the molecular markers of this rare and aggressive disease, focusing on improvements in treatment strategies.
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Affiliation(s)
- Hai‐Yun Wang
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Molecular Diagnostics, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
| | - Xiao‐Yan Wu
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Molecular Diagnostics, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
| | - Xiao Zhang
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Molecular Diagnostics, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
| | - Xin‐Hua Yang
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Molecular Diagnostics, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
| | - Ya‐Kang Long
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Molecular Diagnostics, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
| | - Yan‐Fen Feng
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Pathology, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
| | - Fang Wang
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople's Republic of China
- Department of Molecular Diagnostics, Sun Yat‐Sen University Cancer CenterGuangzhouPeople's Republic of China
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35
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Zhu D, Zhu J, Yu W, Hong P, Fan Y, Zhang Z, Li J, He Q, Han W, Shen C, Jin J. Expression of programmed cell death-ligand 1 in primary testicular diffuse large B cell lymphoma: A retrospective study. Oncol Lett 2019; 18:2670-2676. [PMID: 31452749 PMCID: PMC6676532 DOI: 10.3892/ol.2019.10595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 05/17/2019] [Indexed: 12/21/2022] Open
Abstract
The present study evaluated programmed cell death-ligand 1 (PD-L1) expression in tumor cells and in the tumor microenvironment (TME) and its association with clinical data in primary testicular diffuse large B cell lymphoma (DLBCL). PD-L1 was determined by immunohistochemistry in 30 patients with primary testicular DLBCL and assessed for associations with clinical characteristics, progression-free survival (PFS) and overall survival (OS). The mean patient age was 62.2 years. Overall, 10 (33.3%) patients had advanced-stage (stage III/IV) disease and 14 (46.7%) patients had an International Prognostic Index (IPI) of ≥3. The median follow-up time following orchiectomy was 23.5 months. During this time, 10 (33.3%) patients experienced disease progression and 11 (36.7%) patients succumbed. PD-L1 expression in tumor cells and in the TME was detected in 20 (66.7%) and 13 (43.3%) patients, respectively. PD-L1 expression on tumor cells and in the TME was higher in those at an early stage compared with patients with an advanced stage of disease (P=0.045 and 0.017, respectively). In addition, PD-L1 expression in tumor cells was higher in patients with a low IPI compared with those with a high IPI (P=0.019). A Kaplan-Meier analysis identified no association of PD-L1 expression on tumor cells with PFS (P=0.763) or OS (P=0.531), or of PD-L1 expression in the TME with PFS (P=0.572) or OS (P=0.934). The present study demonstrated that PD-L1 expression in tumor cells and in the TME was higher in patients at an early stage of disease compared with those at an advanced stage, and that PD-L1 expression on tumor cells was higher in patients with a low IPI than in those with a high IPI. Furthermore, PD-L1 expression in tumor cells and in the TME was not associated with PFS or OS.
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Affiliation(s)
- Dongdong Zhu
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Jun Zhu
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Wei Yu
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Peng Hong
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Yu Fan
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Zhongyuan Zhang
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Jun Li
- Department of Pathology, Peking University First Hospital, Beijing 100034, P.R. China
| | - Qun He
- Department of Pathology, Peking University First Hospital, Beijing 100034, P.R. China
| | - Wenke Han
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Cheng Shen
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
| | - Jie Jin
- Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China
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Elbæk MV, Pedersen MØ, Breinholt MF, Reddy A, Love C, Clasen‐Linde E, Knudsen H, Nielsen SL, Gang AO, Høgdall E, Dave S, Nørgaard P. PD‐L1 expression is low in large B‐cell lymphoma with MYC or double‐hit translocation. Hematol Oncol 2019; 37:375-382. [DOI: 10.1002/hon.2664] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/26/2019] [Indexed: 12/28/2022]
Affiliation(s)
| | | | | | - Anupama Reddy
- Duke Cancer Institute and Center for Genomic and Computational Biology Duke University Durham NC USA
| | - Cassandra Love
- Duke Cancer Institute and Center for Genomic and Computational Biology Duke University Durham NC USA
| | | | - Helle Knudsen
- Department of Pathology Herlev and Gentofte Hospital Herlev Denmark
| | | | - Anne Ortved Gang
- Department of Hematology Herlev and Gentofte Hospital Herlev Denmark
| | - Estrid Høgdall
- Department of Pathology Herlev and Gentofte Hospital Herlev Denmark
| | - Sandeep Dave
- Duke Cancer Institute and Center for Genomic and Computational Biology Duke University Durham NC USA
| | - Peter Nørgaard
- Department of Pathology Herlev and Gentofte Hospital Herlev Denmark
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37
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Hao S, Huang G, Feng J, Li D, Wang K, Wang L, Wu Z, Wan H, Zhang L, Zhang J. Non-NF2 mutations have a key effect on inhibitory immune checkpoints and tumor pathogenesis in skull base meningiomas. J Neurooncol 2019; 144:11-20. [DOI: 10.1007/s11060-019-03198-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 05/23/2019] [Indexed: 12/20/2022]
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Harb OA, Kaf RM, Taha HF, Ahmed RZ, Mandour D, Al Attar AZ, Fathy A, Almoregy AS, Osman G, Gertallah LM. Prognostic values and clinical implications of programmed cell death-ligand 1 (PD-L1), fork head transcription factor P-1 (FOXP-1) and signal transducer and activator of transcription-3 (STAT-3) expression in diffuse large B-cell lymphoma (DLBCL); an immunohistochemical study. SURGICAL AND EXPERIMENTAL PATHOLOGY 2019. [DOI: 10.1186/s42047-019-0038-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Context
PD-L1 is an inhibitory ligand that functions as an essential immune checkpoint. FOXP-1 is a member of the FOXP family. STAT-3 plays a critical role in regulation of cell proliferation and survival. The detailed expression of the three markers together in DLBCL tissues and their prognostic value in patients with DLBCL were not fully investigated.
Aim was to assess the expression of PD-L1, FOXP-1 and STAT-3 in diffuse large B-cell lymphoma (DLBCL) and to correlate their expression with the pathological findings, prognostic parameters and clinical implications of patients.
Methods
PD-L1, FOXP-1 and STAT-3 were assessed in DLBCL tissues derived from 50 patients using immunohistochemistry. Patients were followed up for 3 years for response to therapy progression, recurrence and survival.
Results
High PD-L1 expression was associated with bone marrow involvement (p = 0.004), extra-nodal involvement (p = 0.006) and advanced stage (p = 0.003). High FOXP-1 expression was associated with presence of bone marrow involvement and high risk group (p < 0.001). High STAT-3 expression was associated with older age of the patient (p < 0.001), presence of bone marrow involvement (p = 0.002), extra-nodal involvement (p = 0.009), and high risk group (p = 0.005). High expression of PD-L1, FOXP-1 and STAT-3 was related to poor response to therapy, poor OS rate and RFS rates (p < 0.001).
Conclusion
High expression of PD-L1, FOXP-1 and STAT-3 was related poor prognosis in DLBCL patients.
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Qiu L, Zheng H, Zhao X. The prognostic and clinicopathological significance of PD-L1 expression in patients with diffuse large B-cell lymphoma: a meta-analysis. BMC Cancer 2019; 19:273. [PMID: 30917792 PMCID: PMC6437873 DOI: 10.1186/s12885-019-5466-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 03/13/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Programmed cell death receptor 1 ligand 1 (PD-L1) expression in various tumors, including hematologic malignancies, has recently become a research topic of great interest. We performed a meta-analysis to evaluate the prognostic and clinicopathological value of PD-L1 expressed in tumor cells of patients with diffuse large B-cell lymphoma (DLBCL). METHODS Relevant studies were identified from PubMed, EMBASE, Web of Science and the Cochrane Library. The hazard ratio (HR) and 95% confidence interval (95% CI) were used for analyzing survival outcomes, and the odds ratio (OR) was used for analyzing clinicopathological parameters. RESULTS Pooled results showed that tumor cell PD-L1 expression is associated with poor overall survival (OS) (HR = 2.128, 95% CI: 1.341-3.378, P = 0.001), the non-germinal center B-cell-like subtype (OR = 2.891, 95% CI: 2.087-4.003, P < 0.000), high international prognostic index score (3-5) (OR = 1.552, 95% CI: 1.111-2.169, P = 0.010), B symptoms (OR = 1.495, 95% Cl: 1.109-2.015, P = 0.008), positive MUM1 expression (OR = 3.365, 95% Cl: 1.578-7.175, P = 0.002) and negative BCL6 expression (OR = 0.414, 95% Cl: 0.217-0.792, P = 0.008). Sensitivity analysis showed that there was no publication bias among these studies. CONCLUSIONS Our meta-analysis supported the idea that tumor cell PD-L1 expression may represent a promising biomarker for predicting poor prognosis and is associated with adverse clinicopathologic features in DLBCL patients.
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Affiliation(s)
- Liping Qiu
- Department of Hematology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, 310009 China
| | - Hanlu Zheng
- Department of Hematology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, 310009 China
| | - Xiaoying Zhao
- Department of Hematology, The Second Affiliated hospital of Zhejiang University School of Medicine, Hangzhou, 310009 China
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Song MK, Park BB, Uhm J. Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma. Int J Mol Sci 2019; 20:ijms20061326. [PMID: 30884772 PMCID: PMC6470519 DOI: 10.3390/ijms20061326] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/10/2019] [Accepted: 03/12/2019] [Indexed: 02/08/2023] Open
Abstract
In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin’s lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.
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MESH Headings
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- B7-H1 Antigen/analysis
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/immunology
- Humans
- Immunotherapy/methods
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Molecular Targeted Therapy/methods
- Programmed Cell Death 1 Receptor/analysis
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/pathology
- Tumor Escape/drug effects
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Affiliation(s)
- Moo-Kon Song
- Department of Hematology-Oncology, Hanyang University Hanmaeum Changwon Hospital, 51497 Changwon, Korea.
| | - Byeong-Bae Park
- Division of Hematology-Oncology, Department of Internal Medicine, Hanyang University College of Medicine, Hanyang University Seoul Hospital, 04763 Seoul, Korea.
| | - Jieun Uhm
- Division of Hematology-Oncology, Department of Internal Medicine, Hanyang University College of Medicine, Hanyang University Seoul Hospital, 04763 Seoul, Korea.
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41
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Sun C, Jia Y, Wang W, Bi R, Wu L, Bai Q, Zhou X. Integrative analysis of PD-L1 DNA status, mRNA status and protein status, and their clinicopathological correlation, in diffuse large B-cell lymphoma. Histopathology 2019; 74:618-628. [PMID: 30286249 DOI: 10.1111/his.13765] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 09/30/2018] [Indexed: 12/30/2022]
Abstract
AIMS The protein expression of programmed death-ligand 1 (PD-L1) has been recognised as being a biomarker for poor prognosis in diffuse large B-cell lymphoma (DLBCL). The aims of this study were to determine PD-L1 DNA status and mRNA status, and to explore whether they contribute to protein expression and their clinicopathological correlation in DLBCL. METHODS AND RESULTS In this study, we used fluorescence in-situ hybridisation, RNA in-situ hybridisation and immunohistochemistry to determine PD-L1 status at three different levels in 287 DLBCL samples with follow-up. Their correlation and clinical pathological relevance were also analysed. Our results showed that 1.7% (3/175) of patients had PD-L1 DNA amplification, 19.9% (57/287) had high PD-L1 mRNA expression, and 11.8% (34/287) had high PD-L1 protein expression. Both mRNA and protein expression of PD-L1 were significantly higher in non-germinal centre B-cell-like (GCB) DLBCL than in GCB DLBCL (P < 0.05). In addition, the patients with high PD-L1 mRNA or high PD-L1 protein expression but no PD-L1 DNA amplification had significantly poorer overall survival (OS) than those with low PD-L1 expression (P < 0.05). Furthermore, we found that PD-L1 mRNA and PD-L1 protein expression were highly correlated (P = 0.012), which was observed in all three samples with DNA amplification. CONCLUSIONS PD-L1 DNA amplification is a rare event, PD-L1 mRNA is the main contributor to the high PD-L1 protein expression, and the latter two will serve as important biomarkers for predicting the prognosis of DLBCL patients and selecting them for immunotherapy.
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Affiliation(s)
- Chenbo Sun
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Yijun Jia
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
| | - Weige Wang
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China
| | - Rui Bi
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China
| | - Lijing Wu
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China
| | - Qianming Bai
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China.,Department of Oncology, Shanghai Medical College, Shanghai, China.,Institute of Pathology, Fudan University, Shanghai, China
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Tagawa M, Kurashima C, Takagi S, Maekawa N, Konnai S, Shimbo G, Matsumoto K, Inokuma H, Kawamoto K, Miyahara K. Evaluation of costimulatory molecules in dogs with B cell high grade lymphoma. PLoS One 2018; 13:e0201222. [PMID: 30040869 PMCID: PMC6057677 DOI: 10.1371/journal.pone.0201222] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/11/2018] [Indexed: 12/21/2022] Open
Abstract
B cell high grade lymphoma is the most common hematopoietic malignancy in dogs. Although the immune checkpoint molecules, programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and immune checkpoint inhibitors have been evaluated for the treatment of various human lymphoid malignancies, the expression of those molecules and their relationship with prognosis remain unknown in canine lymphoma. The objective of this study was to evaluate the expression of costimulatory molecules on peripheral blood lymphocytes and tumor infiltrating lymphocytes, in addition to associated ligand expression in the lymph nodes of patients with B cell multicentric high grade lymphoma. Eighteen patients diagnosed with B cell high grade lymphoma and nine healthy control dogs were enrolled. Flow cytometric analysis revealed that the expression of PD-1 on CD4+ peripheral and tumor infiltrating lymphocytes and CTLA-4 on CD4+ peripheral lymphocytes was significantly higher in the lymphoma group than in the control group. The expression level of CD80 mRNA was significantly lower in the lymphoma group than in the control group. In contrast, there were no significant differences in PD-L1, PD-L2, and CD86 expression between the groups. Dogs with CTLA-4 levels below the cutoff values, which were determined based on receiver operating characteristic curves, on peripheral CD4+, CD8+, and tumor infiltrating CD4+ lymphocytes had significantly longer survival than dogs with values above the cutoff. Although it is uncertain whether the expression of immune checkpoint molecules affect the biological behavior of canine lymphoma, one possible explanation is that PD-1 and CTLA-4 might be associated with the suppression of antitumor immunity in dogs with B cell high grade lymphoma, particularly through CD4+ T cells.
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Affiliation(s)
- Michihito Tagawa
- Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
- * E-mail:
| | - Chihiro Kurashima
- Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Satoshi Takagi
- Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Veterinary Teaching Hospital, Sapporo, Hokkaido, Japan
| | - Naoya Maekawa
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Satoru Konnai
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Genya Shimbo
- Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Kotaro Matsumoto
- Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Hisashi Inokuma
- Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Keiko Kawamoto
- Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Kazuro Miyahara
- Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
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Castillo JJ, Beltran BE, Miranda RN, Young KH, Chavez JC, Sotomayor EM. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management. Am J Hematol 2018; 93:953-962. [PMID: 29984868 DOI: 10.1002/ajh.25112] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 04/10/2018] [Indexed: 12/29/2022]
Abstract
DISEASE OVERVIEW Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 WHO classification of lymphoid neoplasms. EBV+ DLBCL, NOS, is an aggressive B-cell lymphoma associated with chronic EBV infection, and a poor prognosis with standard chemotherapeutic approaches. DIAGNOSIS The diagnosis is made through a careful pathological evaluation. Detection of EBV-encoded RNA is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, HHV8+ DLBCL, NOS, and EBV+ mucocutaneuos ulcer. RISK-STRATIFICATION The International prognostic index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor. MANAGEMENT Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, has a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.
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Affiliation(s)
- Jorge J. Castillo
- Division of Hematologic Malignancies; Dana-Farber Cancer Institute, Harvard Medical School; Boston Massachusetts
| | - Brady E. Beltran
- Department of Oncology and Radiotherapy; Hospital Nacional Edgardo Rebagliati Martins, and Research Center for Precision Medicine, Universidad San Martin de Porres Medical School; Lima Peru
| | - Roberto N. Miranda
- Department of Hematopathology; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Ken H. Young
- Department of Hematopathology; The University of Texas MD Anderson Cancer Center; Houston Texas
| | - Julio C. Chavez
- Section of Malignant Hematology; Moffitt Cancer Center, University of South Florida; Tampa Florida
| | - Eduardo M. Sotomayor
- Department of Hematology and Oncology; George Washington Cancer Center, George Washington University; Washington DC
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Tremblay-LeMay R, Rastgoo N, Chang H. Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway. J Hematol Oncol 2018; 11:46. [PMID: 29580288 PMCID: PMC5870495 DOI: 10.1186/s13045-018-0589-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 03/11/2018] [Indexed: 02/08/2023] Open
Abstract
Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.
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Affiliation(s)
- Rosemarie Tremblay-LeMay
- Laboratory Hematology/Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Canada
| | - Nasrin Rastgoo
- Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada
| | - Hong Chang
- Laboratory Hematology/Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Canada. .,Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada. .,Department of Talent Highland, First Affiliated Hospital of Xi'an Jiao Tong University, Xian, China. .,Laboratory Hematology, Toronto General Hospital, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada.
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