IL‐2Rα up‐regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T‐cell lymphoma

Wang, Liang; Bi, Xiwen; Zhu, Yujia; He, Yuanyuan; Lai, Qiu-yu; Xia, Zhong‐Jun; Cai, Qingqing

doi:10.1186/s40880-018-0334-8

Cited by 22 publications

(16 citation statements)

References 57 publications

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“…Among all these latent products expressed in ENKL cells, LMP-1 is the main oncogenic protein which inhibits apoptosis and promotes cell-cycle progression, proliferation, migration, and invasion. Further, LMP-1 upregulate the expression of survivin, myc, soluble IL-2 receptor alpha (IL-2R α), and programmed death protein ligand 1 (PD-L1) through multiple downstream signaling pathways, including the MAPK/ERK1/2, JAK/STAT, NF-κB, and PI3K/Akt pathways (12–17).…”

Section: Pathogenic Mechanisms Of Epstein-barr Virus-positive Nk/t-cementioning

confidence: 99%

Epstein-Barr Virus-Positive Natural Killer/T-Cell Lymphoma

Cai

et al. 2019

Front. Oncol.

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Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis. It shows strong association with Epstein-Barr virus infection and occurs more commonly in Asia and Latin America. Various genetic alterations have been identified in ENKL by gene expression profiling and sequencing techniques. The frequent deletion of chromosome 6q21 was reported to lead to the silence of several tumor suppressor genes. Also, there have been novel genetic mutations that were recently uncovered and were found to frequently activate several oncogenic pathways, including the JAK/STAT, NF-κB, and MAPK pathways. Besides, we believe that deregulated single genes and epigenetic dysregulation might be relevant to the mechanism of this disease and thus, may have the potential to shed lights on the development of new therapeutic strategies. The consensus on the standard treatment for ENKL has not yet been currently established. For localized ENKL patients, radiotherapy with concurrent chemotherapy and sequential patterns of chemotherapy and radiotherapy are recommended as first-line therapy. As for advanced or relapsed/refractory ENKL patients, the application of non-anthracycline-containing regimens have significantly improved the clinical outcome, contributing to higher response rate, longer overall survival and progression-free survival. Hematopoietic stem cell transplantation is widely recommended for consolidation after a complete remission or partial remission has been achieved. The anti-programmed death 1 antibody, an immune checkpoint inhibitor, has demonstrated favorable results in treating relapsed or refractory ENKL. Of the current ENKL treatment, researchers are still striving to validate how radiotherapy and chemotherapy should be optimally combined and which of the non-anthracycline-containing regimens is superior. In this review, we summarize the main genetic alterations frequently found in ENKL and their role in providing new insights into the therapeutic targets of this disease, and highlight the recent findings regarding new biologic markers, novel therapeutic strategies applied to this intriguing neoplasm.

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Section: Pathogenic Mechanisms Of Epstein-barr Virus-positive Nk/t-cementioning

confidence: 99%

Epstein-Barr Virus-Positive Natural Killer/T-Cell Lymphoma

Cai

et al. 2019

Front. Oncol.

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“…[5][6][7] In contrast to localized NKTL where front-line therapy may be associated with long-term remission in over 60% of patients, the optimal treatment for advanced NKTL remains a major challenge as 70-80% of the patients experience disease progression or death within 5 years of diagnosis. [8][9][10][11] Asparaginase and pegaspargase are key components of chemotherapeutic regimens for advanced NKTL. [12][13][14] However, treatment-related adverse events (AEs) still remain a significant challenge.…”

Section: Introductionmentioning

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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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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“…Although both pathways are driven by K-ras activation, each pathway appears to operate independently and is likely able to compensate each other if one of them is suppressed. The NF-κB pathway seems mainly activated by extracellular IL-1α (interleukin-1 alpha), whose expression and secretion are enhanced by K-ras [12]. In contrast, the MAPK pathway is stimulated by K-ras activation without the involvement of IL-1α [9].…”

mentioning

confidence: 99%