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Case report: Immune modulation after PD-1 inhibitor therapy in a patient with extranodal NK/T-cell lymphoma secondary to chronic active Epstein-Barr virus disease unveiled by single-cell transcriptomics.

ABSTRACT: Chronic active Epstein-Barr virus disease (CAEBV) is a systemic lymphoproliferative disorder that is closely linked to Epstein-Barr virus (EBV) infection. The clinical course and severity of CAEBV can vary, and in some cases, it can progress to overt lymphoma, which is characterized by extranodal natural killer/T-cell lymphoma (ENKTL) and has a poor clinical outcome. Although anti-programmed cell death protein-1 (PD-1) therapy has shown effectiveness in some patients with EBV-associated disease, it has been less successful in others, and the exact mechanism of action of PD-1 inhibitor therapy in these diseases remains unclear. In this report, we describe a patient who was diagnosed with ENKTL secondary to CAEBV and experienced rapid disease progression accompanied by hyperinflammation after receiving PD-1 inhibitor therapy. Single-cell RNA sequencing revealed a significant increase in the patient's lymphocyte count, especially in natural killer cells, with increased activity following PD-1 inhibitor therapy. This case raises questions about the efficacy and safety of PD-1 inhibitor therapy in patients with EBV-associated diseases.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10149821 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Case report: Immune modulation after PD-1 inhibitor therapy in a patient with extranodal NK/T-cell lymphoma secondary to chronic active Epstein-Barr virus disease unveiled by single-cell transcriptomics.

Wang Yao Y Zhang Minan M Xue Qingfeng Q Zhou Huan H Chen Jie J Wang Hong H Zhang Yaping Y Shi Wenyu W

Frontiers in immunology 20230417

Chronic active Epstein-Barr virus disease (CAEBV) is a systemic lymphoproliferative disorder that is closely linked to Epstein-Barr virus (EBV) infection. The clinical course and severity of CAEBV can vary, and in some cases, it can progress to overt lymphoma, which is characterized by extranodal natural killer/T-cell lymphoma (ENKTL) and has a poor clinical outcome. Although anti-programmed cell death protein-1 (PD-1) therapy has shown effectiveness in some patients with EBV-associated disease, ...[more]

PMID: 37138889

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Project description:Exosomal PD-L1 (exoPD-L1) is reported to be associated with immunosuppression in various cancers. However, its clinical value in extranodal NK/T cell lymphoma (ENKTL) has not been defined yet. We retrospectively evaluated the prognostic value of pretreatment circulating soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) in ENKTL patients treated with VIPD-containing chemotherapy. A total of 107 ENKTL patients, including 101 early stage and 6 advanced stage patients were enrolled in our study. ExoPD-L1 and sPD-L1 in the blood were measured by single molecule array (Simoa) and enzyme-linked immunosorbent assay (ELISA), respectively. Compared with the healthy individuals (n=16), the patients with ENKTL (n=107) exhibited significantly elevated exoPD-L1 and sPD-L1 levels in the blood. High pretreatment plasma exoPD-L1 concentration was associated with higher SUVmax level and recurrence rate. Similarly, high sPD-L1 group was also associated with some adverse clinical parameters, including advanced stage, elevated LDH levels, B symptoms, high IPI score and PINK score. The 5-year progression-free survival (PFS) rate and overall survival (OS) rates were 65.2% and 85.7% for the whole cohort, respectively. Patients with a low pretreatment exoPD-L1 level (simoa signal < 1.2) had 5-year OS and PFS rates of 88.1% and 86.1%, respectively, compared with 56.0%. (P=0.012) and 35.7% (P=0.007) in patients with high exoPD-L1 level (simoa signal > 1.2). The 5-year OS and PFS rates for patients with low sPD-L1 group (< 219 pg/mL) was significantly higher than high sPD-L1 group (≥ 219 pg/mL) (OS, 91.3% vs. 55.5%, P < 0.001; PFS, 68.9% vs. 34.6%, P=0.003). However, no correlation was found between circulating exoPD-L1 and sPD-L1 levels. This is the first study to measure plasma exoPD-L1 level on the Quanterix Simoa platform. Our results proved that circulating exoPD-L1 and sPD-L1 levels were significantly elevated in ENKTL and might be potential biomarkers for predicting the survival outcomes of ENKTL patients.

Project description:The main target cells for Epstein-Barr virus (EBV) infection and persistence are B lymphocytes, although T and NK cells can also become infected. In this paper, we characterize the EBV present in 21 pediatric and adult patients who were treated in France for a range of diseases that involve infection of T or NK cells. Of these 21 cases, 5 pediatric patients (21%) and 11 adult patients (52%) were of Caucasian origin. In about 30% of the cases, some of the EBV genomes contain a large deletion. The deletions are different in every patient but tend to cluster near the BART region of the viral genome. Detailed investigation of a family in which several members have persistent T or NK cell infection by EBV indicates that the virus genome deletions arise or are selected independently in each individual patient. Genome sequence polymorphisms in the EBV in these T or NK cell diseases reflect the geographic origin of the patient and not a distinct type of EBV (the 21 cases studied included examples of both type 1 and type 2 EBV infection). Using virus produced from type 1 or type 2 EBV genomes cloned in bacterial artificial chromosome (BAC) vectors, we demonstrate infection of T cells in cord blood from healthy donors. Our results are consistent with transient infection of some T cells being part of normal asymptomatic infection by EBV in young children. IMPORTANCE EBV contributes to several types of human cancer. Some cancers and nonmalignant lymphoproliferative diseases involving T or NK cells contain EBV. These diseases are relatively frequent in Japan and China and have been shown sometimes to have deletions in the EBV genome in the disease cells. We identify further examples of deletions within the EBV genome associated with T or NK cell diseases, and we provide evidence that the virus genomes with these deletions are most likely selected in the individual cases, rather than being transmitted between people during infection. We demonstrate EBV infection of cord blood T cells by highly characterized, cloned EBV genomes and suggest that transient infection of T cells may be part of normal asymptomatic infection by EBV in young children.

Project description:Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although L-asparaginase-based chemotherapy has resulted in improved response rates, relapse occurs in up to 50% of patients with disseminated disease. There is hence an urgent need for effective targeted therapy, especially for patients with relapsed or refractory disease. Novel insights gleaned from high-throughput molecular and genomic profiling studies in recent years have contributed significantly to the understanding of the molecular biology of ENKTL, which exemplifies many of the hallmarks of cancer. Deregulated pro-proliferative signaling pathways, such as the Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT), platelet-derived growth factor (PDGF), Aurora kinase, MYC, and NF-κB, have been identified as potential therapeutic targets. The discovery of the non-canonical function of EZH2 as a pro-proliferative transcriptional co-activator has shed further light on the pathogenesis of ENKTL. Loss of key tumor suppressor genes located on chromosome 6q21 also plays an important role. The best-studied examples include PR domain zinc finger protein 1(PRDM1), protein tyrosine phosphatase kappa (PTPRK), and FOXO3. Promoter hypermethylation has been shown to result in the downregulation of other tumor suppressor genes in ENKTL, which may be potentially targeted through hypomethylating agents. Deregulation of apoptosis through p53 mutations and upregulation of the anti-apoptotic protein, survivin, may provide a further growth advantage to this tumor. A deranged DNA damage response as a result of the aberration of ataxia telangiectasia-related (ATR) kinases can lead to significant genomic instability and may contribute to chemoresistance of ENKTL. Recently, immune evasion has emerged as a critical pathway for survival in ENKTL and may be a consequence of HLA dysregulation or STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1). Immunotherapy via inhibition of programmed cell death 1 (PD-1)/PD-L1 checkpoint signaling holds great promise as a novel therapeutic option. In this review, we present an overview of the key molecular and pathogenic pathways in ENKTL, organized using the framework of the "hallmarks of cancer" as described by Hanahan and Weinberg, with a focus on those with the greatest translational potential.

Dataset Information

Case report: Immune modulation after PD-1 inhibitor therapy in a patient with extranodal NK/T-cell lymphoma secondary to chronic active Epstein-Barr virus disease unveiled by single-cell transcriptomics.

Publications

Case report: Immune modulation after PD-1 inhibitor therapy in a patient with extranodal NK/T-cell lymphoma secondary to chronic active Epstein-Barr virus disease unveiled by single-cell transcriptomics.

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