Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma

Xiong, Jie; Cui, Bowen; Wang, Nan; Dai, Yuting; Zhang, Hao; Wang, Chao‐Fu; Zhong, Huijuan; Cheng, Shu; Ouyang, Binshen; Hu, Yu; Zhang, Xi; Xu, Bin; Qian, W.; Tao, Rong; Feng, Yan; Hu, Jianda; Hou, Mingxiao; Ma, Xiaofen; Wang, Xin; Liu, Yuanhua; Zhu, Zunmin; Huang, Xiaobin; Liu, Li; Wu, Chongyang; Huang, Li; Shen, Yongchun; Huang, Ruibin; Xu, Jingyan; Wang, Chun; Wu, Depei; Yu, Li; Li, Jianfeng; Xu, Pengpeng; Wang, Li; Huang, Jinyan; Chen, Sai‐Juan; Zhao, Wei‐Li

doi:10.1016/j.ccell.2020.02.005

Cited by 176 publications

(265 citation statements)

References 88 publications

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“…Mutations in ARID1A, KMT2D, TET2, and BCORL1 for case 9 suggested deregulation of the epigenetic control of transcription. This patient seemed to belong to the HEA subtype 28 and was more sensitive to the histone deacetylase inhibitors. ARID1A is a tumor suppressor gene and several studies showed that ARID1A mutations were associated with Fig.…”

Section: Discussionmentioning

confidence: 92%

“…The third patient with poor clinical outcome (case 9) exhibited mutations mainly at the epigenetic modifiers, as previously defined. 28 Gene Ontology-Biological Process (GO-BP) enrichment analysis revealed that the T-cell receptor signaling pathway, immune response-regulating pathway, and immune response-activating pathway were enriched in the group without disease progression (cases 3, 4, 5, and 6) ( Supplementary Fig. 4).…”

Section: Patientsmentioning

confidence: 99%

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Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

Cai

Huang

et al. 2020

Sig Transduct Target Ther

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Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m2 (day 1), gemcitabine 1 g/m2 (days 1 and 8) and oxaliplatin 130 mg/m2 (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

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Section: Discussionmentioning

confidence: 92%

Section: Patientsmentioning

confidence: 99%

Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

Cai

Huang

et al. 2020

Sig Transduct Target Ther

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“…Natural killer/T-cell lymphomas (NKTCL) are invariably infected with EBV, and EBV-infected lymphoma cells upregulate PD-L1 expression [ 37 ]. Recent data have also revealed distinct molecular subtypes of NKTCL, one of which is of clinical relevance and associates to a subtype with alterations of the immune modulator JAK-STAT mutations/amplification of the 9p24.1/PD-L1/2 locus [ 136 ]. Adult T-cell leukemia/lymphoma (ATLL), an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) [ 137 ], carries a high mutational burden of genes, including the T-cell receptor, NF- κ B, and immune surveillance mechanisms [ 138 ].…”

Section: Peripheral T Cell Lymphomas (Ptcl)mentioning

confidence: 99%

Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

Apostolidis

Sayyed

Darweesh

et al. 2020

Journal of Immunology Research

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Cancer cells escape immune recognition by exploiting the programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) immune checkpoint axis. Immune checkpoint inhibitors that target PD-1/PD-L1 unleash the properties of effector T cells that are licensed to kill cancer cells. Immune checkpoint blockade has dramatically changed the treatment landscape of many cancers. Following the cancer paradigm, preliminary results of clinical trials in lymphoma have demonstrated that immune checkpoint inhibitors induce remarkable responses in specific subtypes, most notably classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, while in other subtypes, the results vary considerably, from promising to disappointing. Lymphomas that respond to immune checkpoint inhibitors tend to exhibit tumor cells that reside in a T-cell-rich immune microenvironment and display constitutive transcriptional upregulation of genes that facilitate innate immune resistance, such as structural variations of the PD-L1 locus, collectively referred to as T-cell-inflamed lymphomas, while those lacking such characteristics are referred to as noninflamed lymphomas. This distinction is not necessarily a sine qua non of response to immune checkpoint inhibitors, but rather a framework to move the field forward with a more rational approach. In this article, we provide insights on our current understanding of the biological mechanisms of immune checkpoint evasion in specific subtypes of B-cell and T-cell non-Hodgkin lymphomas and summarize the clinical experience of using inhibitors that target immune checkpoints in these subtypes. We also discuss the phenomenon of hyperprogression in T-cell lymphomas, related to the use of such inhibitors when T cells themselves are the target cells, and consider future approaches to refine clinical trials with immune checkpoint inhibitors in non-Hodgkin lymphomas.

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“…In addition, JAK3, STAT3, and STAT5B mutations leading to the constitutive activation of the JAK/STAT pathway have been reported in ENKTL [75][76][77][78][79]. Xiong et al [80] also demonstrated presence of JAK2, JAK3, STAT3, STAT5A, and STAT5B mutations/ amplifications although their mutational frequency varies between different studies and ranges from 0 to 35% [67]. Other factors such as inactivation of PTPRK by gene deletion and aberrant promoter hypermethylation also results in constitutive activation of JAK/STAT pathway [81], suggesting the diverse molecular mechanisms underlying the activation of JAK/STAT pathway.…”

Section: Extranodal Nk/t Cell Lymphoma Nasal Typementioning

confidence: 99%

“…More recently, integrated analysis of the genomic and transcriptomic features has been used to define three molecular subtypes of NK/T cell lymphoma, termed TSIM, MB, and HEA subtype [80]. TSIM NK/T cell lymphoma seem to arise from NK cells, whereas MB and HEA subtypes may arise from T cells.…”

Section: Extranodal Nk/t Cell Lymphoma Nasal Typementioning

confidence: 99%

Molecular insights into pathogenesis and targeted therapy of peripheral T cell lymphoma

Xie

Zeng

et al. 2020

Exp Hematol Oncol

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Peripheral T-cell lymphomas (PTCLs) are biologically and clinically heterogeneous diseases almost all of which are associated with poor outcomes. Recent advances in gene expression profiling that helps in diagnosis and prognostication of different subtypes and next-generation sequencing have given new insights into the pathogenesis and molecular pathway of PTCL. Here, we focus on a broader description of mutational insights into the common subtypes of PTCL including PTCL not other specified type, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, and extra-nodal NK/T cell lymphoma, nasal type, and also present an overview of new targeted therapies currently in various stages of clinical trials.

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Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma

Cited by 176 publications

References 88 publications

Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

Molecular insights into pathogenesis and targeted therapy of peripheral T cell lymphoma

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