|
1
|
Chantziou A, Brenna C, Ioannidou K, Chen OY, Korkolopoulou P, Antoniadou A, Psichogiou M, Papaioannou M, Tsirigotis P, Foukas PG, de Leval L, Petrovas C. HIV infection is associated with compromised tumor microenvironment adaptive immune reactivity in Hodgkin lymphoma. Blood Adv 2024; 8:6215-6231. [PMID: 39116294 PMCID: PMC11697195 DOI: 10.1182/bloodadvances.2023012116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024] Open
Abstract
ABSTRACT The impact of HIV infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common comorbidities after HIV infection, is not well understood. Here, we have used multiplexed immunofluorescence and spatial transcriptomic analysis to dissect the impact of viral infections (Epstein-Barr virus [EBV] and HIV/EBV) on cHL TME. HIV-EBV+ cHL TME was characterized by higher cell densities of CD8high T cells coexpressing inhibitory receptors (PD-1 and TIGIT), macrophage subsets, and an in situ inflammatory molecular profile associated with increased expression of T-cell receptor (TCR) and B-cell receptor cell signaling pathways than HIV-EBV- cHL TME. Compared with HIV-EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells coexpressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.
Collapse
Affiliation(s)
- Amanda Chantziou
- Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
| | - Cloe Brenna
- Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
| | - Kalliopi Ioannidou
- Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
| | - Oliver Y. Chen
- Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Penelope Korkolopoulou
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Antoniadou
- Fourth Department of Internal Medicine, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Mina Psichogiou
- First Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Papaioannou
- First Department of Internal Medicine, Hematology Unit, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, XX, Greece
| | - Panagiotis Tsirigotis
- Division of Hematology, Second Department of Internal Medicine, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Periklis G. Foukas
- Second Department of Pathology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Laurence de Leval
- Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
| | - Constantinos Petrovas
- Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
| |
Collapse
|
|
2
|
Song W, Gao Y, Wu J, Li H, Shi Z, Gong C, Zhang Z, Li Z, Zhang M. LMP1 enhances aerobic glycolysis in natural killer/T cell lymphoma. Cell Death Dis 2024; 15:604. [PMID: 39164228 PMCID: PMC11335758 DOI: 10.1038/s41419-024-06999-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024]
Abstract
Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment.
Collapse
Affiliation(s)
- Wenting Song
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuyang Gao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jiazhuo Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongwen Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhuangzhuang Shi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Gong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zihe Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
3
|
Yeo YY, Qiu H, Bai Y, Zhu B, Chang Y, Yeung J, Michel HA, Wright K, Shaban M, Sadigh S, Nkosi D, Shanmugam V, Rock P, Tung Yiu SP, Cramer P, Paczkowska J, Stephan P, Liao G, Huang AY, Wang H, Chen H, Frauenfeld L, Mitra B, Gewurz BE, Schürch CM, Zhao B, Nolan GP, Zhang B, Shalek AK, Angelo M, Mahmood F, Ma Q, Burack WR, Shipp MA, Rodig SJ, Jiang S. Epstein-Barr Virus Orchestrates Spatial Reorganization and Immunomodulation within the Classic Hodgkin Lymphoma Tumor Microenvironment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.05.583586. [PMID: 38496566 PMCID: PMC10942289 DOI: 10.1101/2024.03.05.583586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Classic Hodgkin Lymphoma (cHL) is a tumor composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells nested within a T-cell rich inflammatory immune infiltrate. cHL is associated with Epstein-Barr Virus (EBV) in 25% of cases. The specific contributions of EBV to the pathogenesis of cHL remain largely unknown, in part due to technical barriers in dissecting the tumor microenvironment (TME) in high detail. Herein, we applied multiplexed ion beam imaging (MIBI) spatial pro-teomics on 6 EBV-positive and 14 EBV-negative cHL samples. We identify key TME features that distinguish between EBV-positive and EBV-negative cHL, including the relative predominance of memory CD8 T cells and increased T-cell dysfunction as a function of spatial proximity to HRS cells. Building upon a larger multi-institutional cohort of 22 EBV-positive and 24 EBV-negative cHL samples, we orthogonally validated our findings through a spatial multi-omics approach, coupling whole transcriptome capture with antibody-defined cell types for tu-mor and T-cell populations within the cHL TME. We delineate contrasting transcriptomic immunological signatures between EBV-positive and EBV-negative cases that differently impact HRS cell proliferation, tumor-immune interactions, and mecha-nisms of T-cell dysregulation and dysfunction. Our multi-modal framework enabled a comprehensive dissection of EBV-linked reorganization and immune evasion within the cHL TME, and highlighted the need to elucidate the cellular and molecular fac-tors of virus-associated tumors, with potential for targeted therapeutic strategies.
Collapse
|
|
4
|
Xu X, Zhu N, Zheng J, Peng Y, Zeng MS, Deng K, Duan C, Yuan Y. EBV abortive lytic cycle promotes nasopharyngeal carcinoma progression through recruiting monocytes and regulating their directed differentiation. PLoS Pathog 2024; 20:e1011934. [PMID: 38206974 PMCID: PMC10846743 DOI: 10.1371/journal.ppat.1011934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 02/06/2024] [Accepted: 01/01/2024] [Indexed: 01/13/2024] Open
Abstract
Epstein-Barr virus (EBV) is associated with several types of human cancer including nasopharyngeal carcinoma (NPC). The activation of EBV to the lytic cycle has been observed in advanced NPC and is believed to contribute to late-stage NPC development. However, how EBV lytic cycle promotes NPC progression remains elusive. Analysis of clinical NPC samples indicated that EBV reactivation and immunosuppression were found in advanced NPC samples, as well as abnormal angiogenesis and invasiveness. To investigate the role of the EBV lytic cycle in tumor development, we established a system that consists of two NPC cell lines, respectively, in EBV abortive lytic cycle and latency. In a comparative analysis using this system, we found that the NPC cell line in EBV abortive lytic cycle exhibited the superior chemotactic capacity to recruit monocytes and polarized their differentiation toward tumor-associated macrophage (TAM)-like phenotype and away from DCs, compared to EBV-negative or EBV-latency NPC cells. EBV-encoded transcription activator ZTA is responsible for regulating monocyte chemotaxis and TAM phenotype by up-regulating the expression of GM-CSF, IL-8, and GRO-α. As a result, TAM induced by EBV abortive lytic cycle promotes NPC angiogenesis, invasion, and migration. Overall, this study elucidated the role of the EBV lytic life cycle in the late development of NPC and revealed a mechanism underlying the ZTA-mediated establishment of the tumor microenvironment (TME) that promotes NPC late-stage progression.
Collapse
Affiliation(s)
- Xiaoting Xu
- Laboratory of Clinical, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Nannan Zhu
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Junming Zheng
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yingying Peng
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kai Deng
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chaohui Duan
- Laboratory of Clinical, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Yuan
- Institute for Advanced Medical Research, Shandong University, Jinan, China
| |
Collapse
|
|
5
|
Yu J, Fu L, Zhang Z, Ding L, Hong L, Gao F, Jin J, Feng W, Fu J, Hong P, Xu C. Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study. Clin Exp Med 2023; 23:4585-4595. [PMID: 37910257 DOI: 10.1007/s10238-023-01221-y] [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: 09/18/2023] [Accepted: 10/12/2023] [Indexed: 11/03/2023]
Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05-1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02-1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01-1.2; P = 0.03], tumor necrosis factor beta (TNF-β) [OR: 1.16; 95% CI: 1.02-1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01-1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-β, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.
Collapse
Affiliation(s)
- Jieni Yu
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Leihua Fu
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Zhijian Zhang
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Lina Ding
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Li Hong
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Feidan Gao
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Jing Jin
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Weiying Feng
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Jiaping Fu
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Pan Hong
- Department of Hematology, Shaoxing People's Hospital, Shaoxing, Zhejiang, People's Republic of China
| | - Chao Xu
- Department of Vascular and Hernia Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, People's Republic of China.
| |
Collapse
|
|
6
|
Yang L, Liu G, Li Y, Pan Y. The emergence of tumor-infiltrating lymphocytes in nasopharyngeal carcinoma: Predictive value and immunotherapy implications. Genes Dis 2022; 9:1208-1219. [PMID: 35873027 PMCID: PMC9293699 DOI: 10.1016/j.gendis.2021.07.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 11/09/2022] Open
Abstract
The clinical study of nasopharyngeal carcinoma (NPC) often reveals a large number of lymphocytes infiltrating the primary tumor site. As an important part of the tumor microenvironment, tumor-infiltrating lymphocytes (TILs) do not exist alone but as a complex multicellular population with high heterogeneity. TILs play an extremely significant role in the occurrence, development, invasion and metastasis of NPC. The latest research shows that they participate in tumorigenesis and treatment, and the composition, quantity, functional status and distribution of TILs subsets have good predictive value for the prognosis of NPC patients. TILs are an independent prognostic factor for TNM stage and significantly correlated with better prognosis. Additionally, adoptive immunotherapy using anti-tumor TILs has achieved good results in a variety of solid tumors including NPC. This review evaluates recent clinical and preclinical studies of NPC, summarizes the role of TILs in promoting and inhibiting tumor growth, evaluates the predictive value of TILs, and explores the potential benefits of TILs-based immunotherapy in the treatment of NPC.
Collapse
Affiliation(s)
- Liu Yang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, PR China
| | - Guohong Liu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, PR China
| | - Yirong Li
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, PR China
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, PR China
| |
Collapse
|
|
7
|
Nivolumab for recurrent or metastatic head and neck cancer patients with non-squamous cell carcinoma and/or a primary subsite excluded from CheckMate141, a retrospective study. Oral Oncol 2022; 130:105932. [DOI: 10.1016/j.oraloncology.2022.105932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 04/26/2022] [Accepted: 05/20/2022] [Indexed: 01/22/2023]
|
|
8
|
Macrophage Infiltration Correlates with Genomic Instability in Classic Hodgkin Lymphoma. Biomedicines 2022; 10:biomedicines10030579. [PMID: 35327381 PMCID: PMC8945507 DOI: 10.3390/biomedicines10030579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/26/2022] [Accepted: 02/27/2022] [Indexed: 12/10/2022] Open
Abstract
Hodgkin lymphoma (HL) is a biologically diverse group of lymphoid tumors, which accounts for 1% of all de novo neoplasms in the world’s population. It is divided into two main groups: the more common classic Hodgkin lymphoma (cHL) and the less common nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). cHL is further divided into four subtypes, which differ in morphology and the contents of tumor microenvironment. Macrophages are one of the components of tumor microenvironment known to contribute to creating an immunosuppressive microenvironment, which inhibits the activity of cells expressing granzyme B against tumor cells, even when tumor cells are infected with Epstein–Barr virus (EBV). Our research aimed to explore the association between the specific contents of tumor microenvironment and the genetic anomalies in tumor cells. The presence and the relative percentage of cytotoxic T lymphocytes and macrophages was detected by immunohistochemical staining of the antigens specific for certain cell populations. Fluorescent in situ hybridization was used to detect anomalies in the genome of tumor cells and in situ hybridization was used to detect the presence of EBV. Our results show an association between the number of CD163+ macrophages and the number of TP53 copies or BCL6 gene translocation. Patients who had a higher number of CD163+ macrophages infiltrating tumor tissue and three or higher number of copies of TP53 showed poorer survival. We conclude that the presence of macrophages may contribute to genetic instability in cHL, which drives the progression of cHL and decreases survival of the patients.
Collapse
|
|
9
|
Han S, Tay JK, Loh CJL, Chu AJM, Yeong JPS, Lim CM, Toh HC. Epstein–Barr Virus Epithelial Cancers—A Comprehensive Understanding to Drive Novel Therapies. Front Immunol 2021; 12:734293. [PMID: 34956172 PMCID: PMC8702733 DOI: 10.3389/fimmu.2021.734293] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Epstein–Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour–microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.
Collapse
Affiliation(s)
- Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joshua K. Tay
- Department of Otolaryngology—Head & Neck Surgery, National University of Singapore, Singapore, Singapore
| | | | | | - Joe Poh Sheng Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Ming Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- *Correspondence: Han Chong Toh,
| |
Collapse
|
|
10
|
Bauer M, Jasinski-Bergner S, Mandelboim O, Wickenhauser C, Seliger B. Epstein-Barr Virus-Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies. Cancers (Basel) 2021; 13:cancers13205189. [PMID: 34680337 PMCID: PMC8533749 DOI: 10.3390/cancers13205189] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The Epstein–Barr virus, also termed human herpes virus 4, is a human pathogenic double-stranded DNA virus. It is highly prevalent and has been linked to the development of 1–2% of cancers worldwide. EBV-associated malignancies encompass various structural and epigenetic alterations. In addition, EBV-encoded gene products and microRNAs interfere with innate and adaptive immunity and modulate the tumor microenvironment. This review provides an overview of the characteristic features of EBV with a focus on the intrinsic and extrinsic immune evasion strategies, which contribute to EBV-associated malignancies. Abstract The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome.
Collapse
Affiliation(s)
- Marcus Bauer
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Simon Jasinski-Bergner
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
| | - Ofer Mandelboim
- Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, En Kerem, P.O. Box 12271, Jerusalem 91120, Israel;
| | - Claudia Wickenhauser
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Barbara Seliger
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-(345)-557-1357
| |
Collapse
|
|
11
|
Gong L, Kwong DLW, Dai W, Wu P, Wang Y, Lee AWM, Guan XY. The Stromal and Immune Landscape of Nasopharyngeal Carcinoma and Its Implications for Precision Medicine Targeting the Tumor Microenvironment. Front Oncol 2021; 11:744889. [PMID: 34568077 PMCID: PMC8462296 DOI: 10.3389/fonc.2021.744889] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 08/23/2021] [Indexed: 12/11/2022] Open
Abstract
The evolution of the tumor microenvironment (TME) is a cancer-dependent and dynamic process. The TME is often a complex ecosystem with immunosuppressive and tumor-promoting functions. Conventional chemotherapy and radiotherapy, primarily focus on inducing tumor apoptosis and hijacking tumor growth, whereas the tumor-protective microenvironment cannot be altered or destructed. Thus, tumor cells can quickly escape from extraneous attack and develop therapeutic resistance, eventually leading to treatment failure. As an Epstein Barr virus (EBV)-associated malignancy, nasopharyngeal carcinoma (NPC) is frequently infiltrated with varied stromal cells, making its microenvironment a highly heterogeneous and suppressive harbor protecting tumor cells from drug penetration, immune attack, and facilitating tumor development. In the last decade, targeted therapy and immunotherapy have emerged as promising options to treat advanced, metastatic, recurrent, and resistant NPC, but lack of understanding of the TME had hindered the therapeutic development and optimization. Single-cell sequencing of NPC-infiltrating cells has recently deciphered stromal composition and functional dynamics in the TME and non-malignant counterpart. In this review, we aim to depict the stromal landscape of NPC in detail based on recent advances, and propose various microenvironment-based approaches for precision therapy.
Collapse
Affiliation(s)
- Lanqi Gong
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Dora Lai-Wan Kwong
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Wei Dai
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Pingan Wu
- Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yan Wang
- Department of Pathology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Anne Wing-Mui Lee
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong, SAR China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| |
Collapse
|
|
12
|
Lo AKF, Dawson CW, Lung HL, Wong KL, Young LS. The Role of EBV-Encoded LMP1 in the NPC Tumor Microenvironment: From Function to Therapy. Front Oncol 2021; 11:640207. [PMID: 33718235 PMCID: PMC7947715 DOI: 10.3389/fonc.2021.640207] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/21/2021] [Indexed: 12/19/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. It is also characterized by heavy infiltration with non-malignant leucocytes. The EBV-encoded latent membrane protein 1 (LMP1) is believed to play an important role in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways which collectively promote cell proliferation and survival, angiogenesis, invasiveness, and aerobic glycolysis. LMP1 also affects cell-cell interactions, antigen presentation, and cytokine and chemokine production. Here, we discuss how LMP1 modulates local immune responses that contribute to the establishment of the NPC tumor microenvironment. We also discuss strategies for targeting the LMP1 protein as a novel therapy for EBV-driven malignancies.
Collapse
Affiliation(s)
| | | | - Hong Lok Lung
- Department of Biology, Hong Kong Baptist University, Hong Kong, China
| | - Ka-Leung Wong
- Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| | - Lawrence S. Young
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
| |
Collapse
|
|
13
|
Hopkins R, Xiang W, Marlier D, Au VB, Ching Q, Wu LX, Guan R, Lee B, Chia WK, Wang WW, Wee J, Ng J, Cheong R, Han S, Chu A, Chee CL, Shuen T, Podinger M, Lezhava A, Toh HC, Connolly JE. Monocytic Myeloid-Derived Suppressor Cells Underpin Resistance to Adoptive T Cell Therapy in Nasopharyngeal Carcinoma. Mol Ther 2021; 29:734-743. [PMID: 33038324 PMCID: PMC7854281 DOI: 10.1016/j.ymthe.2020.09.040] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/28/2020] [Accepted: 09/28/2020] [Indexed: 12/18/2022] Open
Abstract
Advanced, late-stage Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) is incurable, and its treatment remains a clinical and therapeutic challenge. Results from a phase II clinical trial in advanced NPC patients employing a combined chemotherapy and EBV-specific T cell (EBVST) immunotherapy regimen showed a response rate of 71.4%. Longitudinal analysis of patient samples showed that an increase in EBV DNA plasma concentrations and the peripheral monocyte-to-lymphocyte ratio negatively correlated with overall survival. These parameters were combined into a multivariate analysis to stratify patients according to risk of death. Immunophenotyping at serial time points showed that low-risk individuals displayed significantly decreased amounts of monocytic myeloid-derived suppressor cells postchemotherapy, which subsequently influenced successful cytotoxic T-lymphocyte (CTL) immunotherapy. Examination of the low-risk group, 2 weeks post-EBVST infusion, showed that individuals with a greater overall survival possessed an increased frequency of CD8 central and effector memory T cells, together with higher levels of plasma interferon (IFN)-γ, and cytotoxic lymphocyte-associated transcripts. These results highlight the importance of the rational selection of chemotherapeutic agents and consideration of their impact on both systemic immune responses and downstream cellular immunotherapy outcomes.
Collapse
Affiliation(s)
- Richard Hopkins
- Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore; Tessa Therapeutics, Singapore 038982, Singapore
| | | | | | - Veonice Bijin Au
- Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore
| | - Qianting Ching
- Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore
| | - Lynn Xue Wu
- Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore
| | - Rujun Guan
- Tessa Therapeutics, Singapore 038982, Singapore
| | - Bernett Lee
- Singapore Immunology Network, Singapore 138648, Singapore
| | - Whay-Kuang Chia
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Who-Whong Wang
- Tessa Therapeutics, Singapore 038982, Singapore; National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Joseph Wee
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Joanna Ng
- Tessa Therapeutics, Singapore 038982, Singapore; National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Rachael Cheong
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Shuting Han
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Axel Chu
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Chit Lai Chee
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Timothy Shuen
- National Cancer Centre Singapore, Singapore 169610, Singapore
| | | | | | - Han Chong Toh
- Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore; Tessa Therapeutics, Singapore 038982, Singapore; National Cancer Centre Singapore, Singapore 169610, Singapore.
| | - John E Connolly
- Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore; Tessa Therapeutics, Singapore 038982, Singapore; Institute of Biomedical Studies, Baylor University, Waco, TX 76712, USA.
| |
Collapse
|
|
14
|
Sahinli H, Akyürek N, Yılmaz M, Kandemir O, Duran AO, Kulaçoğlu S, Uçar G, Acar E, Özet A, Gümüş M, Ç Öksüzoğlu ÖB, Özdemir NY. PD-L1 expression in immune cells is a favorable prognostic factor for nasopharyngeal carcinoma. Indian J Cancer 2020; 58:561-566. [PMID: 33402600 DOI: 10.4103/ijc.ijc_459_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Programmed death-ligand 1 (PD-L1) has been determined as a reliable prognostic factor for various malignancies. In this study, we aimed to determine the prognostic effect of PD-L1 expression in tumor-infiltrating immune cells (TIICs) of nasopharyngeal carcinoma (NPC) patients. Methods Seventy patients diagnosed with non-metastatic NPC were included in the study. PD-L1 expression on immune cells was analyzed by immunohistochemical method. Patients were categorized into two groups according to the PD-L1 expression level in TIICs (level of PD-L1 staining ≥5% positive vs <5% negative). Results Median follow-up period was 34 months (range = 1 - 188). 1 and 2 years survival rate were found as 75% and 63% in PD-L1 negative TIICs group (47%), and 85% and 83% in PD-L1 positive TIICs group (53%), respectively. PD-L1 positivity in immune cells (ICs) was detected in 53% of the patients. The survival rate was found better in the PD- L1 positive group compared to the negative group (P = 0.049). Discussion In conclusion, the survival rate was found significantly better in the PD-L1 positive TIICs group, compared to the negative group.
Collapse
Affiliation(s)
- Hayriye Sahinli
- Department of Oncology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Nalan Akyürek
- Department of Pathology, Gazi University Medical Hospital, Ankara, Turkey
| | - Mukaddes Yılmaz
- Department of Oncology, Gazi University Medical University Hospital, Ankara, Turkey
| | - Olcay Kandemir
- Department of Pathology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
| | - Ayşe Ocak Duran
- Department of Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
| | - Sezer Kulaçoğlu
- Department of Pathology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Gökhan Uçar
- Department of Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Elif Acar
- Department of Pathology, Gazi University Medical Hospital, Ankara, Turkey
| | - Ahmet Özet
- Department of Oncology, Gazi University Medical University Hospital, Ankara, Turkey
| | - Mahmut Gümüş
- Department of Oncology, Medical School of Istanbul Medipol University, Istanbul, Turkey
| | - Ö Berna Ç Öksüzoğlu
- Department of Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Hospital, Ankara, Turkey
| | - Nuriye Y Özdemir
- Department of Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| |
Collapse
|
|
15
|
Russo E, Santoni A, Bernardini G. Tumor inhibition or tumor promotion? The duplicity of CXCR3 in cancer. J Leukoc Biol 2020; 108:673-685. [PMID: 32745326 DOI: 10.1002/jlb.5mr0320-205r] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/23/2020] [Accepted: 04/15/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor tissue includes cancer cells and normal stromal cells such as vascular endothelial cells, connective tissue cells (cancer associated fibroblast, mesenchymal stem cell), and immune cells (tumor-infiltrating lymphocytes or TIL, dendritic cells, eosinophils, basophils, mast cells, tumor-associated macrophages or TAM, myeloid-derived suppressor cells or MDSC). Anti-tumor activity is mainly mediated by infiltration of NK cells, Th1 and CD8+ T cells, and correlates with expression of NK cell and T cell attracting chemokines. Nevertheless, cancer cells hijack tissue homeostasis through secretion of cytokines and chemokines that mediate not only the induction of an inflamed status that supports cancer cell survival and growth, but also the recruitment and/or activation of immune suppressive cells. CXCL9, CXCL10, and CXCL11 are known for their tumor-inhibiting properties, but their overexpression in several hematologic and solid tumors correlates with disease severity, suggesting a role in tumor promotion. The dichotomous nature of CXCR3 ligands activity mainly depends on several molecular mechanisms induced by cancer cells themselves able to divert immune responses and to alter the whole local environment. A deep understanding of the nature of such phenomenon may provide a rationale to build up a CXCR3/ligand axis targeting strategy. In this review, we will discuss the role of CXCR3 in cancer progression and in regulation of anti-tumor immune response and immunotherapy.
Collapse
Affiliation(s)
- Eleonora Russo
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Institute Pasteur-Italia, Rome, Italy
| | - Angela Santoni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Institute Pasteur-Italia, Rome, Italy.,IRCCS, Neuromed, Pozzilli, Isernia, Italy
| | - Giovanni Bernardini
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Institute Pasteur-Italia, Rome, Italy
| |
Collapse
|
|
16
|
Unger MS, Li E, Scharnagl L, Poupardin R, Altendorfer B, Mrowetz H, Hutter-Paier B, Weiger TM, Heneka MT, Attems J, Aigner L. CD8 + T-cells infiltrate Alzheimer's disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav Immun 2020; 89:67-86. [PMID: 32479993 DOI: 10.1016/j.bbi.2020.05.070] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 05/25/2020] [Accepted: 05/26/2020] [Indexed: 12/22/2022] Open
Abstract
Neuroinflammation is a major contributor to disease progression in Alzheimer's disease (AD) and is characterized by the activity of brain resident glial cells, in particular microglia cells. However, there is increasing evidence that peripheral immune cells infiltrate the brain at certain stages of AD progression and shape disease pathology. We recently identified CD8+ T-cells in the brain parenchyma of APP-PS1 transgenic mice being tightly associated with microglia as well as with neuronal structures. The functional role of CD8+ T-cells in the AD brain is however completely unexplored. Here, we demonstrate increased numbers of intra-parenchymal CD8+ T-cells in human AD post-mortem hippocampus, which was replicated in APP-PS1 mice. Also, aged WT mice show a remarkable infiltration of CD8+ T-cells, which was more pronounced and had an earlier onset in APP-PS1 mice. To address their functional relevance in AD, we successfully ablated the pool of CD8+ T-cells in the blood, spleen and brain from 12 months-old APP-PS1 and WT mice for a total of 4 weeks using an anti-CD8 antibody treatment. While the treatment at this time of disease stage did neither affect the cognitive outcome nor plaque pathology, RNAseq analysis of the hippocampal transcriptome from APP-PS1 mice lacking CD8+ T-cells revealed highly altered neuronal- and synapse-related gene expression including an up-regulation for neuronal immediate early genes (IEGs) such as the Activity Regulated Cytoskeleton Associated Protein (Arc) and the Neuronal PAS Domain Protein 4 (Npas4). Gene ontology enrichment analysis illustrated that the biological processes "regulation of neuronal synaptic plasticity" and the cellular components "postsynapses" were over-represented upon CD8+ T-cell ablation. Additionally, Kegg pathway analysis showed up-regulated pathways for "calcium signaling", "long-term potentiation", "glutamatergic synapse" and "axon guidance". Therefore, we conclude that CD8+ T-cells infiltrate the aged and AD brain and that brain CD8+ T-cells might directly contribute to neuronal dysfunction in modulating synaptic plasticity. Further analysis will be essential to uncover the exact mechanism of how CD8+ T-cells modulate the neuronal landscape and thereby contribute to AD pathology.
Collapse
Affiliation(s)
- M S Unger
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - E Li
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - L Scharnagl
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - R Poupardin
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria; Experimental and Clinical Cell Therapy Institute, Paracelsus Medical University, Salzburg, Austria
| | - B Altendorfer
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - H Mrowetz
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | | | - T M Weiger
- Department of Biosciences, University of Salzburg, Salzburg, Austria
| | - M T Heneka
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany
| | - J Attems
- Translational and Clinical Institute, Newcastle University, Newcastle upon Tyne, UK
| | - L Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria; Austrian Cluster for Tissue Regeneration, Austria.
| |
Collapse
|
|
17
|
Tsang C, Lo K, Nicholls JM, Huang S, Tsao S. Pathogenesis of Nasopharyngeal Carcinoma. NASOPHARYNGEAL CARCINOMA 2019:45-64. [DOI: 10.1016/b978-0-12-814936-2.00003-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
18
|
Bond DA, Dotson E, Awan FT, Baiocchi RA, Blum KA, Maddocks K. Febrile Hypotensive Reactions Following ABVD Chemotherapy in Patients With EBV-associated Classical Hodgkin Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2018; 19:e123-e128. [PMID: 30594446 PMCID: PMC7104725 DOI: 10.1016/j.clml.2018.11.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 11/22/2018] [Indexed: 11/28/2022]
Affiliation(s)
- David A Bond
- Department of Internal Medicine, Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Emily Dotson
- Department of Pharmacy, The Ohio State University, Columbus, OH
| | - Farrukh T Awan
- Department of Hematology and Medical Oncology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Robert A Baiocchi
- Department of Internal Medicine, Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Kristie A Blum
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
| | - Kami Maddocks
- Department of Internal Medicine, Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.
| |
Collapse
|
|
19
|
The Microenvironment in Epstein-Barr Virus-Associated Malignancies. Pathogens 2018; 7:pathogens7020040. [PMID: 29652813 PMCID: PMC6027429 DOI: 10.3390/pathogens7020040] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/08/2018] [Accepted: 04/11/2018] [Indexed: 12/27/2022] Open
Abstract
The Epstein–Barr virus (EBV) can cause a wide variety of cancers upon infection of different cell types and induces a highly variable composition of the tumor microenvironment (TME). This TME consists of both innate and adaptive immune cells and is not merely an aspecific reaction to the tumor cells. In fact, latent EBV-infected tumor cells utilize several specific mechanisms to form and shape the TME to their own benefit. These mechanisms have been studied largely in the context of EBV+ Hodgkin lymphoma, undifferentiated nasopharyngeal carcinoma, and EBV+ gastric cancer. This review describes the composition, immune escape mechanisms, and tumor cell promoting properties of the TME in these three malignancies. Mechanisms of susceptibility which regularly involve genes related to immune system function are also discussed, as only a small proportion of EBV-infected individuals develops an EBV-associated malignancy.
Collapse
|
|
20
|
Huang SCM, Tsao SW, Tsang CM. Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma. Cancers (Basel) 2018; 10:E106. [PMID: 29617291 PMCID: PMC5923361 DOI: 10.3390/cancers10040106] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/29/2018] [Accepted: 03/30/2018] [Indexed: 12/15/2022] Open
Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. The coexistence of tumor-infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis. Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. Further investigations are needed to delineate the mechanistic linkage of the interplay between viral and host factors, especially in relation to TME, which can be harnessed in future therapeutic strategies.
Collapse
Affiliation(s)
| | - Sai Wah Tsao
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, HK, China.
| | - Chi Man Tsang
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, HK, China.
| |
Collapse
|
|
21
|
Chiu J, Ernst DM, Keating A. Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma. Front Immunol 2018; 9:267. [PMID: 29491867 PMCID: PMC5817071 DOI: 10.3389/fimmu.2018.00267] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 01/30/2018] [Indexed: 12/21/2022] Open
Abstract
An understanding of interactions within the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL) has helped pave the way to novel immunotherapies that have enabled dormant and tumor-tolerant immune cells to be reactivated. The immunosuppressive nature of the TME in cHL specifically inhibits the proliferation and activity of natural killer (NK) cells, which contributes to tumor immune-escape mechanisms. This deficiency of NK cells begins at the tumor site and progresses systemically in patients with advanced disease or adverse prognostic factors. Several facets of cHL account for this effect on NK cells. Locally, malignant Reed-Sternberg cells and cells from the TME express ligands for inhibitory receptors on NK cells, including HLA-E, HLA-G, and programmed death-ligand 1. The secretion of chemokines and cytokines, including soluble IL-2 receptor (sCD25), Transforming Growth Factor-β, IL-10, CXCL9, and CXCL10, mediates the systemic immunosuppression. This review also discusses the potential reversibility of quantitative and functional NK cell deficiencies in cHL that are likely to lead to novel treatments.
Collapse
Affiliation(s)
- Jodi Chiu
- Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Daniel M Ernst
- Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Armand Keating
- Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada
| |
Collapse
|
|
22
|
Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease. Proc Natl Acad Sci U S A 2017; 114:4751-4756. [PMID: 28351978 DOI: 10.1073/pnas.1701836114] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.
Collapse
|
|
23
|
Jiang X, Feng L, Dai B, Li L, Lu W. Identification of key genes involved in nasopharyngeal carcinoma. Braz J Otorhinolaryngol 2016; 83:670-676. [PMID: 27765529 PMCID: PMC9449222 DOI: 10.1016/j.bjorl.2016.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/05/2016] [Accepted: 09/11/2016] [Indexed: 12/22/2022] Open
Abstract
Introduction Nasopharyngeal carcinoma is the most common cancer originating from the nasopharynx. Objective To study the mechanisms of nasopharyngeal carcinoma, we analyzed GSE12452 microarray data. Methods GSE12452 was downloaded from the Gene Expression Omnibus database and included 31 nasopharyngeal carcinoma samples and 10 normal nasopharyngeal tissue samples. The differentially expressed genes were screened by ANOVA in the PGS package. Using the BiNGO plugin in Cytoscape and pathway enrichment analysis in the PGS package, functional and pathway enrichment analyses were performed separately to predict potential functions of the differentially expressed genes. Furthermore, Transcription factor-differentially expressed gene pairs were searched, and then the transcription factor-differentially expressed gene regulatory network was visualized using Cytoscape software. Results A total of 487 genes were screened as differentially expressed genes between the nasopharyngeal carcinoma samples and the normal nasopharyngeal tissue samples. Enrichment analysis indicated that PTGS2 was involved in the regulation of biological process and small cell lung cancer. ZIC2 and OVOL1 may function in nasopharyngeal carcinoma through targeting significantly up-regulated genes (such as PTGS2, FN1, CXCL9 and CXCL10) in the Transcription factor-differentially expressed gene regulatory network (e.g., ZIC2→PTGS2 and OVOL1→CXCL10). Conclusion PTGS2, FN1, CXCL9, CXCL10, ZIC2 and OVOL1 might play roles in nasopharyngeal carcinoma.
Collapse
Affiliation(s)
- Xue Jiang
- Cangzhou Central Hospital, Department of Otorhinolaryngology, Cangzhou, Hebei, China
| | - Lichun Feng
- Cangzhou Central Hospital, Department of Otorhinolaryngology, Cangzhou, Hebei, China
| | - Baoqiang Dai
- Cangzhou Central Hospital, Department of Otorhinolaryngology, Cangzhou, Hebei, China
| | - Liping Li
- Cangzhou Central Hospital, Department of Otorhinolaryngology, Cangzhou, Hebei, China
| | - Weiwei Lu
- Cangzhou Central Hospital, Department of Otorhinolaryngology, Cangzhou, Hebei, China.
| |
Collapse
|
|
24
|
Aldinucci D, Celegato M, Casagrande N. Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance. Cancer Lett 2016; 380:243-52. [DOI: 10.1016/j.canlet.2015.10.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 10/06/2015] [Accepted: 10/07/2015] [Indexed: 12/22/2022]
|
|
25
|
Dolcetti R. Cross-talk between Epstein-Barr virus and microenvironment in the pathogenesis of lymphomas. Semin Cancer Biol 2015; 34:58-69. [DOI: 10.1016/j.semcancer.2015.04.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 04/22/2015] [Accepted: 04/24/2015] [Indexed: 12/13/2022]
|
|
26
|
Van Raemdonck K, Van den Steen PE, Liekens S, Van Damme J, Struyf S. CXCR3 ligands in disease and therapy. Cytokine Growth Factor Rev 2015; 26:311-27. [DOI: 10.1016/j.cytogfr.2014.11.009] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 11/05/2014] [Indexed: 12/19/2022]
|
|
27
|
Solinas A, Calvisi DF. Lessons from rare tumors: Hepatic lymphoepithelioma-like carcinomas. World J Gastroenterol 2015; 21:3472-3479. [PMID: 25834311 PMCID: PMC4375568 DOI: 10.3748/wjg.v21.i12.3472] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 12/11/2014] [Accepted: 02/05/2015] [Indexed: 02/06/2023] Open
Abstract
In this review we focus on lymphoepithelioma-like hepatocellular carcinomas (LEL-HCC) and lymphoepithelioma-like cholangiocarcinomas (LEL-ICC). Despite their rarity, these tumors are of general interest because of their epidemiological and clinical features, and because they represent a distinct model of interaction between the immune system and neoplastic cells. Approximately half of LEL-HCC arise in the context of chronic hepatitis C virus (HCV) infection and have been described both in Eastern and Western patients. By contrast, LEL-ICC is associated in almost all cases with Epstein-Barr virus (EBV) infection and exhibits the same epidemiological features of EBV related malignancies. Compared with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma of corresponding stage, both LEL-HCC and LEL-ICC are characterized by lower rates of recurrence after surgery and better overall survival. How this behavior is related to distinct genetic alterations and tumor microenvironment is unclear. The pathophysiological mechanisms of lymphoid infiltrations seem to be different among the two groups of tumors. In fact, LEL-HCC frequently arises in the context of inflammatory changes driven by HCV infection, and has been recognized as a variant of classical hepatocellular carcinoma. At variance, lymphocyte recruitment of LEL-ICC is similar to that described in nasopharyngeal carcinoma and gastric LEL, and possibly depends on the expression pattern of latent EBV infection.
Collapse
|
|
28
|
Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T, Guigay J, Pancré V, de Launoit Y, Busson P, Moralès O, Delhem N. Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. J Natl Cancer Inst 2014; 107:363. [PMID: 25505237 DOI: 10.1093/jnci/dju363] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC). METHODS Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided. RESULTS CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4(+)CD25(-) T cells and mediated their conversion into inhibitory CD4(+)CD25(high) cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3(Low) Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75 (P < .001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1). CONCLUSION Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.
Collapse
Affiliation(s)
- Dhafer Mrizak
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Nathalie Martin
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Clément Barjon
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Anne-Sophie Jimenez-Pailhes
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Rami Mustapha
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Toshiro Niki
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Joël Guigay
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Véronique Pancré
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Yvan de Launoit
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Pierre Busson
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG)
| | - Olivier Moralès
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG).
| | - Nadira Delhem
- CNRS UMR 8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR142, Lille, France (DM, NM, RM, VP, YdL, OM, ND); Université Paris-sud, CNRS UMR 8126 and Institut Gustave Roussy, Villejuif, France (CB, ASJP, PB); GalPharma Co., Ltd. 884-3-302, Fuseishi-Cho, Takamatsu-shi, Kagawa 761-8071 Japan (TN); Department of Immunology, Kagawa University. 1750-1 Ikenobe, Miki-Cho, Kagawa 761-0793 Japan (TN); Department of head and Neck Oncology, Institut Gustave Roussy, Villejuif, France (JG).
| |
Collapse
|
|
29
|
Control of the inflammatory response mechanisms mediated by natural and induced regulatory T-cells in HCV-, HTLV-1-, and EBV-associated cancers. Mediators Inflamm 2014; 2014:564296. [PMID: 25525301 PMCID: PMC4267219 DOI: 10.1155/2014/564296] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 06/18/2014] [Accepted: 07/30/2014] [Indexed: 02/07/2023] Open
Abstract
Virus infections are involved in chronic inflammation and, in some cases, cancer development. Although a viral infection activates the immune system's response that eradicates the pathogen mainly through inflammatory mechanisms, it is now recognized that this inflammatory condition is also favorable to the development of tumors. Indeed, it is well described that viruses, such as hepatitis C virus (HCV), Epstein Barr virus (EBV), human papillomavirus (HPV) or human T-cell lymphotropic virus type-1 (HTLV-1), are important risk factors for tumor malignancies. The inflammatory response is a fundamental immune mechanism which involves several molecular and cellular components consisting of cytokines and chemokines that are released by various proinflammatory cells. In parallel to this process, some endogenous recruited components release anti-inflammatory mediators to restore homeostasis. The development of tools and strategies using viruses to hijack the immune response is mostly linked to the presence of regulatory T-cells (Treg) that can inhibit inflammation and antiviral responses of other effector cells. In this review, we will focus on current understanding of the role of natural and induced Treg in the control and the resolution of inflammatory response in HCV-, HTLV-1-, and EBV-associated cancers.
Collapse
|
|
30
|
Prevalence and Prognostic Significance of Epstein–Barr Virus Infection in Classical Hodgkin's Lymphoma: A Meta-analysis. Arch Med Res 2014; 45:417-31. [DOI: 10.1016/j.arcmed.2014.06.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 06/04/2014] [Indexed: 12/21/2022]
|
|
31
|
Liu Y, Sattarzadeh A, Diepstra A, Visser L, van den Berg A. The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component. Semin Cancer Biol 2013; 24:15-22. [PMID: 23867303 DOI: 10.1016/j.semcancer.2013.07.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 06/20/2013] [Accepted: 07/06/2013] [Indexed: 12/19/2022]
Abstract
Classical Hodgkin lymphoma (cHL) is characterized by a minority of tumor cells derived from germinal center B-cells and a vast majority of non-malignant reactive cells. The tumor cells show a loss of B-cell phenotype including lack of the B-cell receptor, which makes the tumor cells vulnerable to apoptosis. To overcome this threat, tumor cells and their precursors depend on anti-apoptotic and growth stimulating factors that are obtained via triggering of multiple membrane receptors. In addition, tumor cells shape the environment by producing a wide variety of chemokines and cytokines. These factors alter the composition of the microenvironment and modulate the nature and effectiveness of the infiltrating cells. The attracted cells enhance the pro-survival and growth stimulating signals for the tumor cells. To escape from an effective anti-tumor response tumor cells avoid recognition by T and NK cells, by downregulation of HLA molecules and modulating NK and T-cell receptors. In addition, the tumor cells produce immune suppressive cytokines that inhibit cytotoxic responses. In this review the relevance of the microenvironment in the pathogenesis of cHL will be discussed.
Collapse
Affiliation(s)
- Yuxuan Liu
- Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
| | - Ahmad Sattarzadeh
- Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
| | - Arjan Diepstra
- Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
| | - Lydia Visser
- Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
| | - Anke van den Berg
- Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
| |
Collapse
|
|
32
|
Gourzones C, Klibi-Benlagha J, Friboulet L, Jlidi R, Busson P. Cellular Interactions in Nasopharyngeal Carcinomas. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013. [DOI: 10.1007/978-1-4614-5947-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
|
|
33
|
Ansell SM, Maurer MJ, Ziesmer SC, Slager SL, Habermann TM, Link BK, Witzig TE, Macon WR, Dogan A, Cerhan JR, Novak AJ. Elevated pretreatment serum levels of interferon-inducible protein-10 (CXCL10) predict disease relapse and prognosis in diffuse large B-cell lymphoma patients. Am J Hematol 2012; 87:865-9. [PMID: 22674570 DOI: 10.1002/ajh.23259] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 05/02/2012] [Indexed: 12/24/2022]
Abstract
Although standard clinical prognostic factors predict outcome in diffuse large B-cell lymphoma (DLBCL), predicting the outcome of patients might be further refined using biological factors. We tested whether serum cytokines could provide prognostic information in DLBCL patients. Thirty cytokines were measured in pretreatment samples from newly diagnosed DLBCL patients using a multiplex ELISA. Sixty-nine patients treated with R-CHOP plus epratuzumab were used in an initial cohort and 185 patients treated with standard R-CHOP served as a subsequent validation cohort. In the initial cohort, elevated serum interleukin-10 [IL-10; hazard ratio (HR) = 6.6, P = 0.022], granulocyte macrophage colony-stimulating factor (HR = 10.8, P= 0.027) and IP-10 (interferon-inducible protein-10, CXCL10; HR = 3.32, P = 0.015) were associated with event-free survival (EFS). An identical analysis of the subsequent validation cohort confirmed that elevated serum levels of IP-10 were strongly associated with a poor EFS (HR = 2.42, P = 0.0007); and also identified interleukin-8 (IL-8; HR = 3.40, P = 0.00002) and interleukin-2 receptor (IL-2R, CD25; HR = 2.59, P = 0.0012) as significantly associated with prognosis. The prognostic significance of elevated IP-10 remained significant after adjustment for the International Prognostic Index (EFS - HR 1.99, P = 0.009, overall survival-HR 1.93, P = 0.021). Elevated pretreatment serum IP-10 levels are therefore associated with an increased likelihood of disease relapse and an inferior survival in patients with DLBCL.
Collapse
MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Murine-Derived/administration & dosage
- Antibodies, Monoclonal, Murine-Derived/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Chemokine CXCL10/blood
- Cohort Studies
- Cyclophosphamide/administration & dosage
- Cyclophosphamide/therapeutic use
- Disease-Free Survival
- Doxorubicin/administration & dosage
- Doxorubicin/therapeutic use
- Female
- Humans
- Lymphoma, Large B-Cell, Diffuse/blood
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Male
- Middle Aged
- Predictive Value of Tests
- Prednisone/administration & dosage
- Prednisone/therapeutic use
- Prognosis
- Recurrence
- Reproducibility of Results
- Rituximab
- Vincristine/administration & dosage
- Vincristine/therapeutic use
- Young Adult
Collapse
Affiliation(s)
- Stephen M Ansell
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
de la Cruz-Merino L, Lejeune M, Nogales Fernández E, Henao Carrasco F, Grueso López A, Illescas Vacas A, Pulla MP, Callau C, Álvaro T. Role of immune escape mechanisms in Hodgkin's lymphoma development and progression: a whole new world with therapeutic implications. Clin Dev Immunol 2012; 2012:756353. [PMID: 22927872 PMCID: PMC3426211 DOI: 10.1155/2012/756353] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 06/05/2012] [Indexed: 12/31/2022]
Abstract
Hodgkin's lymphoma represents one of the most frequent lymphoproliferative syndromes, especially in young population. Although HL is considered one of the most curable tumors, a sizeable fraction of patients recur after successful upfront treatment or, less commonly, are primarily resistant. This work tries to summarize the data on clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on therapeutical strategies. The recent advances in our understanding of HL biology and immunology show that infiltrated immune cells and cytokines in the tumoral microenvironment may play different functions that seem tightly related with clinical outcomes. Strategies aimed at interfering with the crosstalk between tumoral Reed-Sternberg cells and their cellular partners have been taken into account in the development of new immunotherapies that target different cell components of HL microenvironment. This new knowledge will probably translate into a change in the antineoplastic treatments in HL in the next future and hopefully will increase the curability rates of this disease.
Collapse
Affiliation(s)
- Luis de la Cruz-Merino
- Clinical Oncology Department, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Jöhrer K, Hofbauer SW, Zelle-Rieser C, Greil R, Hartmann TN. Chemokine-dependent B cell-T cell interactions in chronic lymphocytic leukemia and multiple myeloma - targets for therapeutic intervention? Expert Opin Biol Ther 2012; 12:425-41. [PMID: 22332909 DOI: 10.1517/14712598.2012.664128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Chemokines and their receptors play essential roles in the development, maintenance and proper functioning of the immune system. B cell-T cell interactions are modulated by chemokines. In B cell malignancies, these interactions may have tumor-promoting consequences. AREAS COVERED This review summarizes physiological B cell-T cell interactions and discusses their pathological role in the onset and progression of B cell malignancies with a special focus on chronic lymphocytic leukemia and multiple myeloma. Experimental data on chemokine-guided B cell-T cell actions in B cell malignancies from murine models as well as in vitro data are summarized and their potential as future therapeutic targets is critically discussed. EXPERT OPINION Direct or indirect targeting of chemokine receptors involved in localization and T-cell-dependent activation of B lymphocytes can provide strong synergisms with conventional or immunomodulatory therapies by disrupting the microenvironmental conditions necessary for survival and proliferation of malignant B lymphocytes. However, further knowledge of these interactions between B and T cells is needed.
Collapse
Affiliation(s)
- Karin Jöhrer
- Tyrolean Cancer Research Institute, Innsbruck, Austria.
| | | | | | | | | |
Collapse
|
|
36
|
Gourzones C, Barjon C, Busson P. Host-tumor interactions in nasopharyngeal carcinomas. Semin Cancer Biol 2012; 22:127-36. [PMID: 22249142 DOI: 10.1016/j.semcancer.2012.01.002] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 12/29/2011] [Accepted: 01/03/2012] [Indexed: 12/13/2022]
Abstract
Like other human solid tumors, nasopharyngeal carcinoma (NPC) is a tissue and a systemic disease as much as a cell disease. Tumor cell population in NPC is highly heterogeneous. Heavy infiltration by non-malignant leucocytes results at least in part from the production of abundant inflammatory cytokines by the malignant epithelial cells. There is indirect evidence that interactions between stromal and malignant cells contribute to tumor development. Peripheral blood samples collected from NPC patients contain multiple products derived from the tumor, including cytokines, non-cytokine tumor proteins, tumor exosomes and viral nucleic acids. These products represent a potential source of biomarkers for assessment of tumor aggressiveness, indirect exploration of cellular interactions and monitoring of tumor response to therapeutic agents. Most NPC patients are immunocompetent with evidence of active humoral and cellular immune responses against EBV-antigens at the systemic level. Tumor development is facilitated by local immunosuppressive factors which are not fully understood. Local accumulation of regulatory T-cells is probably one important factor. At least two NPC tumor products are suspected to contribute to their expansion, the cytokine CCL20 and the tumor exosomes carrying galectin 9. In the future, new therapeutic modalities will probably aim at breaking immune tolerance or at blocking cellular interactions critical for tumor growth.
Collapse
Affiliation(s)
- Claire Gourzones
- Université Paris-Sud-11, CNRS-UMR 8126 and Institut de cancérologie Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France
| | | | | |
Collapse
|
|
37
|
Chauhan V, Howland M, Kutzner B, McNamee JP, Bellier PV, Wilkins RC. Biological effects of alpha particle radiation exposure on human monocytic cells. Int J Hyg Environ Health 2011; 215:339-44. [PMID: 22153871 DOI: 10.1016/j.ijheh.2011.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Revised: 10/06/2011] [Accepted: 11/08/2011] [Indexed: 01/18/2023]
Abstract
Radon ((222)Rn) gas produces decay progeny that emits high energy alpha (α)-particles. Epidemiological studies have shown that exposure to (222)Rn is linked with elevated risk of developing lung cancer, however clear mechanisms leading to such effects have not been delineated. Cytokines play a critical role in inflammation and their dysregulated production often contributes to disease pathogenesis. In this study, Bio-plex multiplex technology was employed to investigate modulations of 27 pro-inflammatory cytokines following exposure of human monocytic cells to 1.5 Gy of α-particle radiation. Concurrently, DNA damage was assessed by examining the formation of phosphorylated H2A histone family X (γ-H2AX) sites. Of the 27 cytokines assessed, 4 cytokines were shown to be statistically downregulated by ∼2 fold relative to the untreated controls and included the interleukin (IL) family of proteins (IL-2, IL-15 and IL-17) and macrophage inflammatory protein 1 beta (MIP-1b). Interferon-inducible protein-12 (IP-12), vascular endothelial growth factor and regulated on activation normal T cell expressed and secreted (RANTES) were shown to be high expressors and upregulated. Cells irradiated with α-particles ranging from 0.27 to 2.14 Gy showed statistically significant, dose-dependant increases in γ-H2AX formation. These data suggest that α-particle radiation causes dysregulation in the production of a number of pro-inflammatory cytokines and results in significant DNA damage.
Collapse
Affiliation(s)
- Vinita Chauhan
- Consumer and Clinical Radiation Protection Bureau, Health Canada, ON, Canada K1A 0K9. Vinita
| | | | | | | | | | | |
Collapse
|
|
38
|
Abstract
Hodgkin disease (HD) is a malignancy of primarily B lymphocytes that has the unique ability to cause immunodeficiency, as well as provide immune evasion mechanisms to avoid self-destruction. In this review, the authors discuss Hodgkin disease, its association with Epstein-Barr virus (EBV), the immune deficiency caused by HD, and tumor immune evasion mechanisms. Specifically, the authors closely evaluate the roles of regulatory T cells in HD, cytotoxic T cells, cytokine and chemokine secretion, down-regulation of Fas ligand, and indoleamine 2,3-dioxygenase (IDO) secretion.
Collapse
|
|
39
|
Gene Expression Profiling for In Silico Microdissection of Hodgkin's Lymphoma Microenvironment and Identification of Prognostic Features. Adv Hematol 2011; 2011:485310. [PMID: 21197104 PMCID: PMC3004394 DOI: 10.1155/2011/485310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Accepted: 11/11/2010] [Indexed: 11/30/2022] Open
Abstract
Gene expression profiling studies based on DNA microarrays have demonstrated their ability to define the interaction pathways between neoplastic and nonmalignant stromal cells in cancer tissues. During the past ten years, a number of approaches including microdissection have tried to resolve the variability in DNA microarray measurements stemming from cancer tissue sample heterogeneity. Another approach, designated as virtual or in silico microdissection, avoids the laborious and time-consuming step of anatomic microdissection. It consists of confronting the gene expression profiles of complex tissue samples to those of cell lines representative of different cell lineages, different differentiation stages, or different signaling pathways. This strategy has been used in recent studies aiming to analyze microenvironment alterations using gene expression profiling of nonmicrodissected classical Hodgkin lymphoma tissues in order to generate new prognostic factors. These recent contributions are detailed and discussed in the present paper.
Collapse
|
|
40
|
Chang KP, Chang YT, Wu CC, Liu YL, Chen MC, Tsang NM, Hsu CL, Chang YS, Yu JS. Multiplexed immunobead-based profiling of cytokine markers for detection of nasopharyngeal carcinoma and prognosis of patient survival. Head Neck 2010; 33:886-97. [DOI: 10.1002/hed.21557] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2010] [Indexed: 11/10/2022] Open
|
|
41
|
Kamper P, Bendix K, Hamilton-Dutoit S, Honoré B, Nyengaard JR, d'Amore F. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin's lymphoma. Haematologica 2010; 96:269-76. [PMID: 21071500 DOI: 10.3324/haematol.2010.031542] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Classical Hodgkin's lymphoma is characterized by a minority of neoplastic cells surrounded by a heterogeneous background population of non-neoplastic cells including lymphoma-associated macrophages. High levels of expression of both the monocyte/macrophage lineage-associated antigens CD68 and CD163 have been suggested to have pro-tumor effects. The aim of our study was to correlate expression of CD68 and CD163 with the clinico-pathological features and prognosis of a cohort of patients with previously untreated Hodgkin's lymphoma. DESIGN AND METHODS A tissue microarray was constructed from paraffin-embedded tumor tissues from 288 cases of classical Hodgkin's lymphoma. CD68 and CD163 expression was assessed immunohistochemically and the degree of macrophage infiltration within the tumor was scored using point grid counting. Clinical data were obtained from clinical records. RESULTS The patients' median age was 37 years (range, 6-86 years). The male to female ratio was 1.2. In classical Hodgkin's lymphoma (n = 288) high CD68 and CD163 expression correlated, at the univariate level, with poorer overall survival (P=0.002 and P=0.03, respectively) and event-free survival (P=0.03 and P=0.04, respectively). At the multivariate level, high CD68 expression remained significantly predictive of overall survival (P=0.004). In addition, we demonstrated that both high CD68 and CD163 expression were associated with the presence of Epstein-Barr virus in the neoplastic cells (P=0.001 and P=0.0002, respectively). CONCLUSIONS In classical Hodgkin's lymphoma, high expression of the macrophage/monocyte-related antigens CD68 and CD163 correlates with adverse outcome and with the presence of Epstein-Barr virus in the tumor cell population.
Collapse
Affiliation(s)
- Peter Kamper
- Department of Hematology, Aarhus University Hospital, Tage Hansens Gade 2 DK-8000, Aarhus C, Denmark.
| | | | | | | | | | | |
Collapse
|
|
42
|
Shin SY, Nam JS, Lim Y, Lee YH. TNFα-exposed bone marrow-derived mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines. J Biol Chem 2010; 285:30731-40. [PMID: 20650898 DOI: 10.1074/jbc.m110.128124] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are often recruited to solid tumors, integrate into the tumor stroma, and contribute to tumor development. TNFα is a major inflammatory cytokine present in the tumor microenvironment and has a profound influence on the progression of tumor development. This study was aimed to investigate the role of BM-MSCs in tumor promotion in response to TNFα. Quantitative real-time PCR arrays show that diverse cytokines/chemokines were induced in TNFα-treated BM-MSCs; in particular, CXCR3 ligand chemokines, including CXCL9, CXCL10, and CXCL11, were potently induced. A serial and site-directed mutation analysis in the CXCL9, CXCL10, and CXCL11 promoters revealed that NF-κB binding elements were responsible for TNFα-induced promoter activation of CXCR3 ligand chemokines. TNFα stimulated NF-κB activity, and ectopic expression of NF-κB enhanced TNFα-induced promoter activities of the CXCR3 ligand chemokines. Gel shift and supershift assays showed that NF-κB was associated with CXCR3 ligand chemokine promoters in response to TNFα treatment. All three CXCR3 ligand chemokines enhanced the migration and invasive motility of MDA-MB-231 breast cancer cells expressing CXCR3. Treatment of MDA-MB-231 cells with CXCL10 activated small GTPase of Rho family proteins, such as RhoA and Cdc42. CXCL9-, CXCL10-, or CXCL11-induced invasive capability of MDA-MB-231 cells was completely abrogated in the presence of a neutralizing anti-CXCR3 antibody in the culture medium. Moreover, CXCL9, CXCL10, and CXCL11 stimulated the expression of MMP-9, but not MMP-2, in MDA-MB-231 cells. These results suggest that BM-MSCs promote the locomotion of breast cancer cells through CXCR3 ligand-mediated actin rearrangement by TNFα in the tumor microenvironment.
Collapse
Affiliation(s)
- Soon Young Shin
- Institute of Biomedical Science and Technology, Konkuk University Hospital, Seoul 143-729, Korea
| | | | | | | |
Collapse
|
|
43
|
Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood 2010; 115:4455-63. [PMID: 20299510 DOI: 10.1182/blood-2009-10-251082] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Primary effusion lymphoma (PEL) constitutes a subset of non-Hodgkin lymphoma whose incidence is highly increased in the context of HIV infection. Kaposi sarcoma-associated herpesvirus is the causative agent of PEL. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and survival, and this pathway is dysregulated in many different cancers, including PEL, which display activated PI3K, Akt, and mammalian target of rapamycin (mTOR) kinases. PELs rely heavily on PI3K/Akt/mTOR signaling, are dependent on autocrine and paracrine growth factors, and also have a poor prognosis with reported median survival times of less than 6 months. We compared different compounds that inhibit the PI3K/Akt/mTOR pathway in PEL. Although compounds that modulated activity of only a single pathway member inhibited PEL proliferation, the use of a novel compound, NVP-BEZ235, that dually inhibits both PI3K and mTOR kinases was significantly more efficacious in culture and in a PEL xenograft tumor model. NVP-BEZ235 was effective at low nanomolar concentrations and has oral bioavailability. We also report a novel mechanism for NVP-BEZ235 involving the suppression of multiple autocrine and paracrine growth factors required for lymphoma survival. Our data have broad applicability for the treatment of cytokine-dependent tumors with PI3K/mTOR dual inhibitors.
Collapse
|
|
44
|
Abstract
Up to 40% of Hodgkin lymphoma (HL) cases are associated with the Epstein-Barr virus (EBV). Clonal viral genomes can be found in the HL tumor cells, the Hodgkin Reed-Sternberg cells (HRS). The latent infection results in expression of the viral oncogenes LMP1 and LMP2A which contribute to generate the particular phenotype of the HRS cells. EBV does not only undergo epigenetic changes of its genome during latency, but also induces epigenetic changes in the host genome. The presence of EBV may alter the composition and activity of the immune cells surrounding the HRS cells. EBV favours a Th1 reaction, but this attempt at a cell mediated immune response appears to be ineffective. The presence of EBV in HL is associated with several clinicopathological characteristics: It is more frequent in cases with mixed cellular histology, in males, in children and older adults, and in developing countries, while the young-adult onset HL of nodular sclerosis type in industrialized countries is typically EBV-negative. Countries in the Mediterranean area often show an intermediate epidemiological pattern. Recent studies suggest a genetic predisposition to develop EBV-associated HL. Circulating EBV-DNA may serve as a biomarker to monitor response to therapy, and eventually, EBV will become a target for therapeutic intervention also in HL.
Collapse
|
|
45
|
Gacci M, Serni S, Lapini A, Vittori G, Alessandrini M, Nesi G, Palli D, Carini M. CXCR3-B Expression Correlates With Tumor Necrosis Extension in Renal Cell Carcinoma. J Urol 2009; 181:843-8. [DOI: 10.1016/j.juro.2008.10.063] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2008] [Indexed: 11/16/2022]
Affiliation(s)
- Mauro Gacci
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Sergio Serni
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Alberto Lapini
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Gianni Vittori
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Marco Alessandrini
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Gabriella Nesi
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Domenico Palli
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| | - Marco Carini
- From the Departments of Urology (MG, SS, AL, GV, MC) and Pathology (GN) and Center for Tumor Study and Prevention (DP), University of Florence, Florence, Italy
| |
Collapse
|
|
46
|
Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood 2008; 113:2765-3775. [PMID: 19096012 DOI: 10.1182/blood-2008-07-168096] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The outcome of classical Hodgkin lymphoma (cHL) patients may be related to the tumor microenvironment, which in turn may be influenced by Epstein-Barr virus (EBV) infection. To characterize the cHL microenvironment, a set of 63 cHL tissue samples was profiled using DNA microarrays. Their gene expression profile differed from that of histiocyte T cell-rich B-cell lymphoma (H/TCRBCL) samples that were used as controls, mainly due to high expression of PDCD1/PD-1 in H/TCRBCL. EBV(+) cHL tissues could be distinguished from EBV(-) samples by a gene signature characteristic of Th1 and antiviral responses. Samples from cHL patients with favorable outcome overexpressed genes specific for B cells and genes involved in apoptotic pathways. An independent set of 146 cHL samples was analyzed using immunohistochemistry. It showed a significant adverse value in case of high percentage of either TIA-1(+)-reactive cells or topoisomerase-2(+) tumor cells, whereas high numbers of BCL11A(+), FOXP3(+), or CD20(+) reactive cells had a favorable influence. Our results suggest an antitumoral role for B cells in the cHL microenvironment and a stronger stromal influence of the PD1 pathway in H/TCRBCL than cHL. The observation of Th1/ antiviral response in EBV(+) cHL tissues provides a basis for novel treatment strategies.
Collapse
|
|
47
|
Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood 2008; 113:1957-66. [PMID: 19005181 DOI: 10.1182/blood-2008-02-142596] [Citation(s) in RCA: 340] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes. Here, we sought to determine whether galectin-9-carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9-containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3-binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBV-specific CD4(+) cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC.
Collapse
|
|
48
|
Datta D, Contreras AG, Grimm M, Waaga-Gasser AM, Briscoe DM, Pal S. Calcineurin inhibitors modulate CXCR3 splice variant expression and mediate renal cancer progression. J Am Soc Nephrol 2008; 19:2437-46. [PMID: 18832436 DOI: 10.1681/asn.2008040394] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Calcineurin inhibitors (CNI) are used to prevent inflammatory diseases and allograft rejection. However, little is known about the mechanism(s) underlying their ability to promote the development and recurrence of cancer. Recent studies suggested that the chemokine receptor CXCR3 may play important roles in tumorigenesis. CXCR3 has two splice variants with opposite functions: CXCR3-A promotes cell proliferation, and CXCR3-B inhibits cell growth. Here, we explored the effects of CNI on the expression and function of CXCR3 splice variants. Compared with normal renal tissues and renal epithelial cells, human renal cancer tissues and renal cancer cell lines demonstrated higher expression of CXCR3-A and markedly lower expression of CXCR3-B. In human renal cancer cells (786-0 and Caki-1) and renal epithelial cells, CNI markedly downregulated the expression of CXCR3-B, whereas expression of CXCR3-A was unchanged. This CNI-mediated downregulation of CXCR3-B resulted in increased proliferation and migration of renal cancer cells; CNI-mediated cell proliferation involved signaling through G(i) proteins, perhaps via CXCR3-A. Finally, it was observed that CNI treatment increased the growth of human renal tumors in vivo, and the expression of CXCR3-B was significantly decreased in these tumors. In summary, these observations suggest that CNI may mediate the progression of human renal cancer by downregulating CXCR3-B and by promoting proliferative signals, likely through CXCR3-A. Targeting CXCR3 splice variants or the signaling pathways downstream of CXCR3 receptors may provide a therapeutic strategy for the prevention of CNI-mediated renal cancer progression.
Collapse
Affiliation(s)
- Dipak Datta
- Division of Nephrology and Transplantation Research Center, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | | | | | | | | | | |
Collapse
|
|
49
|
Niens M, Visser L, Nolte IM, van der Steege G, Diepstra A, Cordano P, Jarrett RF, Te Meerman GJ, Poppema S, van den Berg A. Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J Haematol 2008; 140:527-36. [PMID: 18275430 DOI: 10.1111/j.1365-2141.2007.06964.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hodgkin lymphoma (HL) is characterized by a minority of neoplastic Hodgkin-Reed Sternberg (HRS) cells surrounded by a non-neoplastic reactive infiltrate. As immunological mechanisms appear to be crucial in classical HL pathogenesis, altered serum chemokine levels might be related to disease activity. Serum levels of nine chemokines were examined in 163 untreated HL patients and 334 controls. We investigated single nucleotide polymorphisms (SNPs) for association with serum CCL17 (thymus and activation-regulated chemokine, TARC) levels and HL susceptibility. Serum CCL17 and CCL22 (macrophage-derived chemokine, MDC) levels were significantly increased in 82% and 57% of the HL patients. Nodular sclerosis cases showed increased serum CCL17 and CCL22 levels (P < 0.001) and serum levels were correlated with Ann Arbor stage. Of nine patients with pre- and post-treatment serum samples, the majority showed decreased CCL17 and CCL22 levels after treatment. HRS cells expressed CCL17 and CCL22 in 77% and 75% of 74 cases. Three SNPs showed a trend of increased serum CCL17 levels with minor alleles in controls, but were not associated with HL susceptibility. CCL17 and CCL22 were the only chemokines with increased serum levels in the vast majority of HL patients, which provides further insight into the molecular mechanism(s) leading to infiltrations of reactive lymphocytes in HL.
Collapse
Affiliation(s)
- Marijke Niens
- Department of Medical Genetics, Unviersity Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Carbone A, Gloghini A, Cabras A, Elia G. The Germinal centre-derived lymphomas seen through their cellular microenvironment. Br J Haematol 2008; 145:468-80. [PMID: 19344401 DOI: 10.1111/j.1365-2141.2009.07651.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The human lymph node is a complex tissue resulting from the microenvironmental organisation of different cell populations linked by topographical and/or functional relationships. Germinal centres (GCs) of lymphoid follicles contain a meshwork of follicular dendritic cells in addition to B-cells and some CD4(+) T cells. Moreover, there is a sharp demarcation around the whole follicle centre, which is highlighted by fibroblastic reticulum cells. On the whole, GC exerts a role in B cell physiology and malignancy. In GC-derived lymphomas, gene expression profiling studies have raised the possibility that survival of the affected patients may be associated with signatures preferentially expressed in non-malignant T cells and macrophages and/or dendritic cells. Immunohistological analyses in lymphoma biopsy samples have confirmed that the biological behaviour and tumour progression may be influenced by the tumour microenvironment. This review will examine GC-derived lymphomas, including follicular lymphomas, Hodgkin lymphomas and angioimmunoblastic T-cell lymphoma, through their integrated cellular microenvironment, highlighting those findings which may serve as a useful surrogate marker for tumour diagnosis or tumour progression, together with key molecules involved in tumour development.
Collapse
Affiliation(s)
- Antonino Carbone
- Department of Pathology and Laboratory and Transfusion Medicine, Istituto Nazionale Tumori, Milano, Italy.
| | | | | | | |
Collapse
|