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Liu Q, Song M, Wang Y, Zhang P, Zhang H. CCL20-CCR6 signaling in tumor microenvironment: Functional roles, mechanisms, and immunotherapy targeting. Biochim Biophys Acta Rev Cancer 2025; 1880:189341. [PMID: 40348067 DOI: 10.1016/j.bbcan.2025.189341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 05/01/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Chemokine CC motif ligand 20 (CCL20) is a molecule with immunomodulatory properties that is involved in the regulation of diseases such as chronic inflammation, autoimmune diseases, and cancer. It operates by binding to its specific receptor, CC chemokine receptor type 6 (CCR6), and activating a complex intracellular signaling network. Building on its established role in inflammatory diseases, recent research has expanded our understanding of CCL20 to encompass its critical contributions to the tumor microenvironment (TME), highlighting its significance in cancer progression. Numerous studies have emphasized its prominent role in regulating immune responses. Consequently, Monoclonal antibodies against CCL20 and inhibitors of CCR6 have been successfully developed to block downstream signaling, making the CCL20-CCR6 axis a promising and critical target in the TME. This offers potential immunotherapeutic strategies for cancers. In this review, we summarize the biological consequences of CCL20-CCR6 mediated signaling, its role and mechanisms in the TME, and its potential applications. We suggest that the CCL20-CCR6 axis may be a novel biomarker for tumor diagnosis and prognosis, as well as a therapeutic target in various cancers.
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Affiliation(s)
- Qi Liu
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Mingyuan Song
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yan Wang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China.
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2
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Chen N, Zong Y, Yang C, Li L, Yi Y, Zhao J, Zhao X, Xie X, Sun X, Li N, Jiang L. KMO-driven metabolic reconfiguration and its impact on immune cell infiltration in nasopharyngeal carcinoma: a new avenue for immunotherapy. Cancer Immunol Immunother 2025; 74:75. [PMID: 39891699 PMCID: PMC11787144 DOI: 10.1007/s00262-024-03928-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 12/18/2024] [Indexed: 02/03/2025]
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC), a malignant epithelial tumor, is characterized by a complex tumor microenvironment (TME) and closely associated with metabolic dysfunction. Mitochondrial metabolism plays a crucial role in supporting the rapid proliferation of tumor cells. However, the specific response of mitochondria to the NPC microenvironment and their role in regulating the metabolic heterogeneity of the tumor remain poorly understood. METHODS Tissue samples and corresponding clinicopathological data were collected from 72 primary NPC patients and 36 non-tumor controls. Histological analysis, coupled with public transcriptomic database interrogation, was utilized to investigate mitochondrial dynamics and metabolism across different cell types. Characterizing the interactions within the tumor-immune microenvironment (TME), we identified mitochondrial genes associated with prognosis in NPC. Additionally, we explored the relationship between key mitochondrial genes, the TME, and the response to immunotherapy. RESULTS Malignant epithelial cells in NPC exhibited altered mitochondrial metabolism, including dysregulation of amino acid and glucose metabolism, when compared to non-malignant cells. The mitochondrial-related hub gene KMO was significantly downregulated in NPC tissues relative to normal controls. Low expression of KMO was associated with poorer survival outcomes in patients. Furthermore, KMO expression was negatively correlated with DNA repair mechanisms and hypoxia. In addition, KMO levels were inversely associated with the upregulation of both oxidative phosphorylation (OXPHOS) and glycolysis pathways within the NPC tumor microenvironment (TME). Single-cell transcriptomic analysis revealed that KMO was primarily expressed in B cells, with some contribution from myeloid cells. Importantly, KMO levels positively correlated with the infiltration of various immune cell populations, including B cells, T cells, and macrophages, as well as inflammatory signatures. Further investigation indicated that individuals with elevated KMO expression may exhibit heightened sensitivity to immune checkpoint blockade (ICB) therapy compared to those with lower KMO expression. CONCLUSION The mitochondrial hub gene KMO plays a pivotal role in regulating mitochondrial metabolism and modulating the immune microenvironment in NPC. As a potential prognostic biomarker, KMO may offer valuable predictive insights, and targeting KMO could represent a promising therapeutic strategy for NPC, potentially enhancing the efficacy of immunotherapies.
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Affiliation(s)
- Nijun Chen
- Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuan Zong
- Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Chen Yang
- Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lei Li
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yang Yi
- Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Jiawen Zhao
- Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoyu Zhao
- School of Stomatology, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Xianfei Xie
- Hainan Branch, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qionghai, 571434, China
- Department of Orthopedics Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Xingmei Sun
- Department of Otolaryngology & Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Ning Li
- Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
| | - Liting Jiang
- Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
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Huang X, Tang Y. Unveiling the complex double-edged sword role of exosomes in nasopharyngeal carcinoma. PeerJ 2025; 13:e18783. [PMID: 39822977 PMCID: PMC11737332 DOI: 10.7717/peerj.18783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/09/2024] [Indexed: 01/19/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelium of the nasopharynx. Given its late diagnosis, NPC raises serious considerations in Southeast Asia. In addition to resistance to conventional treatment that combines chemotherapy and radiation, NPC has high rates of metastasis and frequent recurrence. Exosomes are small membrane vesicles at the nanoscale that transport physiologically active compounds from their source cell and have a crucial function in signal transmission and intercellular message exchange. The exosomes detected in the tissues of NPC patients have recently emerged as a potential non-invasive liquid biopsy biomarker that plays a role in controlling the tumor pathophysiology. Here, we take a look back at what we know so far about the complex double-edged sword role of exosomes in NPC. Exosomes could serve as biomarkers and therapeutic agents, as well as the molecular mechanisms by which they promote cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance, and chemotherapy resistance in NPC. Furthermore, we go over some of the difficulties and restrictions associated with exosome use. It is anticipated that this article would provide the reference for the apply of exosomes in clinical practice.
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Affiliation(s)
- Xueyan Huang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yuedi Tang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China
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Wang H, Zhan Y, Luo J, Wang W, Fan S. Unveiling immune resistance mechanisms in nasopharyngeal carcinoma and emerging targets for antitumor immune response: tertiary lymphoid structures. J Transl Med 2025; 23:38. [PMID: 39789621 PMCID: PMC11721552 DOI: 10.1186/s12967-024-05880-7] [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: 07/31/2024] [Accepted: 11/13/2024] [Indexed: 01/12/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in China, commonly associated with undifferentiated cell types and Epstein-Barr virus (EBV) infection. The presence of intense lymphocytic infiltration and elevated expression of programmed cell death ligand 1(PD-L1) in NPC highlights its potential for immunotherapy, yet current treatment outcomes remain suboptimal. In this review, we explore the tumor microenvironment of NPC to better understand the mechanisms of resistance to immunotherapy, evaluate current therapeutic strategies, and pinpoint emerging targets, such as tertiary lymphoid structures (TLSs), that could enhance treatment outcomes and prognostic accuracy. TLSs have demonstrated positive prognostic value in NPC, making them a promising target for future therapies. This review summarizes the key characteristics of TLSs and latest research in the context of NPC. We are optimistic that targeting TLSs could improve immunotherapy outcomes for NPC patients, ultimately leading to more effective treatment strategies and better patient survival.
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Affiliation(s)
- Huilin Wang
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China
| | - Yuting Zhan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China
| | - Jiadi Luo
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China
| | - Weiyuan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China.
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Cai M, Wang Y, Ma H, Yang L, Xu Z. Advances and challenges in immunotherapy for locally advanced nasopharyngeal carcinoma. Cancer Treat Rev 2024; 131:102840. [PMID: 39426201 DOI: 10.1016/j.ctrv.2024.102840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/23/2024] [Accepted: 10/09/2024] [Indexed: 10/21/2024]
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor of the head and neck, with approximately 70 % of patients being diagnosed at a locally advanced stage. Despite the responsiveness to radiotherapy and chemotherapy, the 5-year survival rate of locally advanced NPC (LANPC) remains at approximately 80 %. Hence, there is an urgent need for novel treatment strategies to improve the prognosis of patients with LANPC. Numerous studies have illustrated the efficacy of immune checkpoint inhibitors (ICIs) in recurrent/metastatic NPC. Hence, the potential of immunotherapy for LANPC is under investigation. Using the Web of Clinical Trials, we identified 84 relevant trials exploring immunotherapy for NPC, encompassing 17 trials focusing on ICIs for LANPC. Preliminary findings from several trials suggest that adding ICIs into the primary treatment for LANPC significantly enhances the objective response rate and progression-free survival, with manageable safety profiles. However, the type, dosage, and timing of integration (induction phase, concurrent phase, and adjuvant phase) of ICIs into standard primary treatment of LANPC varies among these trials and further researches are warranted. This review provides an overview of immunotherapy principles in NPC, discusses recent advances and challenges associated with ICIs in the primary treatment for LANPC derived from published and ongoing clinical trials, and outlines the current landscape of other immunotherapies in LANPC, such as adoptive cell therapy, immunomodulatory agents, and tumor vaccines in LANPC. These insights aim to inform clinical practice and guide future researches.
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Affiliation(s)
- Miaoying Cai
- Shenzhen University Medicine School, Shenzhen University, 518060, Shenzhen, Guangdong, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, 518053, Shenzhen, Guangdong, China
| | - Yifu Wang
- Shenzhen University Medicine School, Shenzhen University, 518060, Shenzhen, Guangdong, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, 518053, Shenzhen, Guangdong, China
| | - Huangrong Ma
- Shenzhen University Medicine School, Shenzhen University, 518060, Shenzhen, Guangdong, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, 518053, Shenzhen, Guangdong, China
| | - Li Yang
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, 518053, Shenzhen, Guangdong, China
| | - Zhiyuan Xu
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, 518053, Shenzhen, Guangdong, China.
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Liang C, Kan J, Wang J, Lu W, Mo X, Zhang B. Nasopharyngeal carcinoma-associated inflammatory cytokines: ongoing biomarkers. Front Immunol 2024; 15:1448012. [PMID: 39483474 PMCID: PMC11524805 DOI: 10.3389/fimmu.2024.1448012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 10/02/2024] [Indexed: 11/03/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a neoplasm related to inflammation; the expression of cytokines, such as CCL3, CCL4, CCL20, IL-1α, IL-1β, IL-6, IL-8, and IL-10, among others, is presumed to be associated with NPC occurrence and development. Therefore, the circulating levels of these cytokines may be potential biomarkers for assessing tumor aggressiveness, exploring cellular interactions, and monitoring tumor therapeutic responses. Numerous scholars have comprehensively explored the putative mechanisms through which these inflammatory factors affect NPC progression and therapeutic responses. Moreover, investigations have focused on elucidating the correlation between the systemic levels of these cytokines and the incidence and prognosis of NPC. This comprehensive review aims to delineate the advancements in research concerning the relationship between inflammatory factors and NPC while considering their prospective roles as novel prognostic and predictive biomarkers in the context of NPC.
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Affiliation(s)
- Chuwen Liang
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun Kan
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jingli Wang
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wei Lu
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaoyan Mo
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bei Zhang
- TCM&VIP Inpatient Department, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Chen Z, Ling J, Zhang S, Feng Y, Xie Y, Liu X, Hou T. Predicting the overall survival and progression-free survival of nasopharyngeal carcinoma patients based on hemoglobin, albumin, and globulin ratio and classical clinicopathological parameters. Head Neck 2024; 46:2600-2615. [PMID: 38646952 DOI: 10.1002/hed.27777] [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: 11/14/2023] [Revised: 03/16/2024] [Accepted: 04/08/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Serum biomarkers have a significant impact on the prediction of treatment outcomes in patients diagnosed with nasopharyngeal carcinoma (NPC). The primary aim of this study was to develop and validate a nomogram that incorporates hemoglobin, albumin, and globulin ratio (HAGR) and clinical data to accurately forecast treatment outcomes in patients with NPC. METHODS A total of 796 patients diagnosed with NPC were included in the study. RESULTS The results of the multivariate Cox analysis revealed that TNM stage and HAGR were found to be significant independent prognostic factors for OS and PFS. Furthermore, the utilization of the nomogram demonstrated a significant improvement in the evaluation of OS, PFS compared with the eighth TNM staging system. Additionally, the implementation of Kaplan-Meier curves and decision curve analysis curves further confirmed the discriminability and clinical effectiveness of the nomogram. CONCLUSIONS The HAGR, an innovative prognostic factor grounded in the realm of immunonutrition, has emerged as a promising prognostic marker for both OS and PFS in individuals afflicted with NPC.
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Affiliation(s)
- Zui Chen
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jie Ling
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Sujuan Zhang
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yuhua Feng
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yangchun Xie
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xianling Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tao Hou
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
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Chen C, Zhang Y, Wu X, Shen J. The role of tertiary lymphoid structure and B cells in nasopharyngeal carcinoma: Based on bioinformatics and experimental verification. Transl Oncol 2024; 41:101885. [PMID: 38295746 PMCID: PMC10846412 DOI: 10.1016/j.tranon.2024.101885] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/02/2023] [Accepted: 01/15/2024] [Indexed: 02/07/2024] Open
Abstract
OBJECTIVE Transcriptomic characteristics and prognosis of tertiary lymphoid structures (TLS) and infiltrating B cells in nasopharyngeal carcinoma (NPC) remain unclear. Here, NPC transcriptomic data and clinical samples were used to investigate the role of infiltrating B cells and TLS in NPC. METHODS We investigated the gene expression and infiltrating immune cells of NPC patients and further investigated the clinical relevance of B cell and TLS signatures. Transcriptional features of infiltrating B cell subsets were revealed by single-cell RNA sequencing (scRNA-seq) analysis. Immunohistochemical (IHC) and HE staining were performed to validate the clinical relevance of infiltrating B cells and TLS in NPC samples. RESULTS 27 differentially expressed immune-related genes (IRGs) associated with prognosis were identified, including B cell marker genes CD19 and CD79B. The higher B cells and TLS signature scores were associated with better outcomes and early pathological staging in 88 NPC patients. ScRNA-seq identified five distinct B cell subsets in NPC, including the BC-4 cluster associated with poor outcomes and the BC-0 cluster associated with better outcomes. EBV infection was positively associated with the formation of TLS. Furthermore, experimental results showed that the infiltration of B cells in NPC tissues was higher than that of normal tissues, and the density of TLS in an early stage of NPC was higher than that in advanced-stage TLS. CONCLUSION Our findings demonstrate the functional importance of distinct B cell subsets in the prognosis of NPC. Additionally, we confirmed that B cells and TLS may serve as prognostic biomarkers of survival for NPC patients.
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Affiliation(s)
- Chujun Chen
- Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, PR China
| | - Yan Zhang
- Pathology Dept., The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China
| | - Xiaoting Wu
- School of Bioscience and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, PR China
| | - Juan Shen
- School of Bioscience and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, PR China.
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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.
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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
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Yang X, Ren H, Li Z, Peng X, Fu J. Combinations of radiotherapy with immunotherapy in nasopharyngeal carcinoma. Int Immunopharmacol 2023; 125:111094. [PMID: 37871379 DOI: 10.1016/j.intimp.2023.111094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND The treatment of nasopharyngeal carcinoma (NPC) is currently based on concurrent chemoradiotherapy. The prognosis of early NPC is better, while the prognosis of advanced NPC is poor. Immunotherapy is becoming increasingly commonly employed in clinical practice as a new strategy for treating malignant tumors. It has shown promising results in the treatment of certain malignant tumors, making it a current clinical research hotspot. METHODS This review summarizes the current immunotherapy on NPC, highlighting the application of immunotherapy and radiotherapy in the treatment of NPC. RESULTS X-rays can either increase or suppress anti-tumor immune responses through various pathways and mechanisms. Immune checkpoint inhibitors can usually enhance X-ray-induced anti-tumor immune responses. Detecting the immune checkpoint markers and tumor mutation markers, and the functional status of effector cells in patients can aid in the development of individualized treatment that improves the treatment efficacy with reducing drug resistance and adverse reactions. The development of a multivalent vaccine for NPC will help improve the efficacy of the vaccine. Combining techniques that increase the tumor antigens release, such as radiotherapy and oncolytic virus vaccines, may enhance the ability of the immune response. CONCLUSIONS To shed further light on the application of immunotherapy in NPC, large pooled studies must accumulate sufficient cases with detailed exposure data.
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Affiliation(s)
- Xiaojing Yang
- Department of Radiation Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hanru Ren
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, Shanghai, China
| | - Zhen Li
- Department of Radiation Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xue Peng
- Department of Breast Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Fu
- Department of Radiation Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Lefebvre A, Trioën C, Renaud S, Laine W, Hennart B, Bouchez C, Leroux B, Allorge D, Kluza J, Werkmeister E, Grolez GP, Delhem N, Moralès O. Extracellular vesicles derived from nasopharyngeal carcinoma induce the emergence of mature regulatory dendritic cells using a galectin-9 dependent mechanism. J Extracell Vesicles 2023; 12:e12390. [PMID: 38117000 PMCID: PMC10731827 DOI: 10.1002/jev2.12390] [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: 04/21/2023] [Revised: 11/02/2023] [Accepted: 11/13/2023] [Indexed: 12/21/2023] Open
Abstract
Nasopharyngeal carcinoma-derived small extracellular vesicles (NPCSEVs) have an immunosuppressive impact on the tumour microenvironment. In this study, we investigated their influence on the generation of tolerogenic dendritic cells and the potential involvement of the galectin-9 (Gal9) they carry in this process. We analysed the phenotype and immunosuppressive properties of NPCSEVs and explored the ability of DCs exposed to NPCSEVs (NPCSEV-DCs) to regulate T cell proliferation. To assess their impact at the pathophysiological level, we performed real-time fluorescent chemoattraction assays. Finally, we analysed phenotype and immunosuppressive functions of NPCSEV-DCs using a proprietary anti-Gal9 neutralising antibody to assess the role of Gal9 in this effect. We described that NPCSEV-DCs were able to inhibit T cell proliferation despite their mature phenotype. These mature regulatory DCs (mregDCs) have a specific oxidative metabolism and secrete high levels of IL-4. Chemoattraction assays revealed that NPCSEVs could preferentially recruit NPCSEV-DCs. Finally, and very interestingly, the reduction of the immunosuppressive function of NPCSEV-DCs using an anti-Gal9 antibody clearly suggested an important role for vesicular Gal9 in the induction of mregDCs. These results revealed for the first time that NPCSEVs promote the emergence of mregDCs using a galectin-9 dependent mechanism and open new perspectives for antitumour immunotherapy targeting NPCSEVs.
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Affiliation(s)
- Anthony Lefebvre
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Camille Trioën
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Sarah Renaud
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - William Laine
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277 ‐ CANTHER ‐ Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | | | - Clément Bouchez
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Bertrand Leroux
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | | | - Jérôme Kluza
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277 ‐ CANTHER ‐ Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | - Elisabeth Werkmeister
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 – UAR 2014 – PLBSLilleFrance
| | - Guillaume Paul Grolez
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Nadira Delhem
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Olivier Moralès
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277 ‐ CANTHER ‐ Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
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12
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Siak PY, Heng WS, Teoh SSH, Lwin YY, Cheah SC. Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect. J Transl Med 2023; 21:786. [PMID: 37932756 PMCID: PMC10629096 DOI: 10.1186/s12967-023-04673-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 10/29/2023] [Indexed: 11/08/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC patients such that EBV serological tests were used to diagnose and screen NPC patients. On the other hand, as the downstream effectors of oncogenic mechanisms, the promitotic pathways can potentially be exploited therapeutically. With the apparent heterogeneity and distinct molecular aberrations of NPC tumor, the focus has turned into a more personalized treatment in NPC. Herein in this comprehensive review, we depict the current status of screening, diagnosis, treatment, and prevention in NPC. Subsequently, based on the limitations on those aspects, we look at their potential improvements in moving towards the path of precision medicine. The importance of recent advances on the key molecular aberration involved in pathogenesis of NPC for precision medicine progression has also been reported in the present review. Besides, the challenge and future outlook of NPC management will also be highlighted.
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Affiliation(s)
- Pui Yan Siak
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, 71010, Port Dickson, Negeri Sembilan, Malaysia
| | - Win Sen Heng
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, 71010, Port Dickson, Negeri Sembilan, Malaysia
| | - Sharon Siew Hoon Teoh
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, 71010, Port Dickson, Negeri Sembilan, Malaysia
| | - Yu Yu Lwin
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Medicine, Mandalay, Myanmar
| | - Shiau-Chuen Cheah
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, 71010, Port Dickson, Negeri Sembilan, Malaysia.
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13
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Li CZ, Qiang YY, Liu ZJ, Zheng LS, Peng LX, Mei Y, Meng DF, Wei WW, Chen DW, Xu L, Lang YH, Xie P, Peng XS, Wang MD, Guo LL, Shu DT, Ding LY, Lin ST, Luo FF, Wang J, Li SS, Huang BJ, Chen JD, Qian CN. Ulinastatin inhibits the metastasis of nasopharyngeal carcinoma by involving uPA/uPAR signaling. Drug Dev Res 2023; 84:1468-1481. [PMID: 37534761 DOI: 10.1002/ddr.22098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/31/2023] [Accepted: 07/20/2023] [Indexed: 08/04/2023]
Abstract
Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.
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Affiliation(s)
- Chang-Zhi Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Medical School, Pingdingshan University, Pingdingshan, China
| | - Yuan-Yuan Qiang
- Ningxia Key Laboratory for Cerebrocranical Disease, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Zhi-Jie Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiotherapy, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong, China
| | - Li-Sheng Zheng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Li-Xia Peng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Mei
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dong-Fang Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wen-Wen Wei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Dong-Wen Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liang Xu
- Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan-Hong Lang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ping Xie
- Department of Radiation Oncology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xing-Si Peng
- Department of Radiation Oncology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ming-Dian Wang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ling-Ling Guo
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Di-Tian Shu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Liu-Yan Ding
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Si-Ting Lin
- The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi, China
| | - Fei-Fei Luo
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing Wang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Sha-Sha Li
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bi-Jun Huang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | | | - Chao-Nan Qian
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Guangzhou Concord Cancer Center, Guangzhou, China
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14
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Zhu DQ, Su C, Li JJ, Li AW, Luv Y, Fan Q. Update on Radiotherapy Changes of Nasopharyngeal Carcinoma Tumor Microenvironment. World J Oncol 2023; 14:350-357. [PMID: 37869238 PMCID: PMC10588496 DOI: 10.14740/wjon1645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/11/2023] [Indexed: 10/24/2023] Open
Abstract
The utilization of radiotherapy (RT) serves as the principal approach for managing nasopharyngeal carcinoma (NPC). Consequently, it is imperative to investigate the correlation between the radiation microenvironment and radiation resistance in NPC. PubMed and China National Knowledge Infrastructure (CNKI) databases were accessed to perform a search utilizing the English keywords "nasopharyngeal cancer", "radiotherapy", and "microenvironment". The search time spanned from the establishment of the database until January 20, 2023. A total of 82 articles were included. The post-radiation tumor microenvironment (TME), or the radiation microenvironment, includes several components, such as the radiation-immune microenvironment and the radiation-hypoxic microenvironment. The radiation-immune microenvironment includes various factors like immune cells, signaling molecules, and extracellular matrix. RT can reshape the TME, leading to immune responses with both cytotoxic effects (T cells, B cells, natural killer (NK) cells) and immune escape mechanisms (regulatory T cells (Tregs), macrophages). RT enhances immune responses through DNA release, type I interferons, and immune cell recruitment. Radiation-hypoxic microenvironment affects metabolism and molecular changes. RT-induced hypoxia causes vascular changes, fibrosis, and vessel compression, leading to tissue hypoxia. Hypoxia activates hypoxia-inducible factor (HIF)-1α/2α, promoting angiogenesis and glycolysis in tumor cells. TME changes due to hypoxia also involve immune suppressive cells like myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Tregs. The radiation microenvironment is involved in radiation resistance and holds a significant effect on the prognosis of patients with NPC. Exploring the radiation microenvironment provides new insights into RT and NPC research.
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Affiliation(s)
- Dao Qi Zhu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Chao Su
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jing Jun Li
- NanFang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ai Wu Li
- NanFang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ying Luv
- NanFang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Qin Fan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
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15
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Huang H, Yao Y, Deng X, Huang Z, Chen Y, Wang Z, Hong H, Huang H, Lin T. Immunotherapy for nasopharyngeal carcinoma: Current status and prospects (Review). Int J Oncol 2023; 63:97. [PMID: 37417358 PMCID: PMC10367053 DOI: 10.3892/ijo.2023.5545] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/29/2023] [Indexed: 07/08/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial tumor located in the nasopharynx and is highly associated with Epstein‑Barr virus (EBV) infection. Although radiotherapy alone can cure ~90% of patients with early‑stage disease, >70% of patients with NPC have locoregionally advanced or metastatic disease at the first diagnosis due to the insidious and aggressive nature of NPC. After comprehensive radiochemotherapy, 20‑30% of patients with advanced NPC still fail treatment, mainly due to recurrence and/or metastasis (R/M). Conventional salvage treatments, such as radiotherapy, chemotherapy and surgery, are suboptimal and frequently accompanied by severe adverse effects and limited efficacy. In recent years, immunotherapy has emerged as a promising treatment modality for R/M NPC. An increasing number of clinical studies have investigated the safety and efficacy of immunotherapy for advanced NPC and have shown considerable progress. In the present review, the rationale for the use of immunotherapy to treat NPC was summarized and the current status, progress and challenges of NPC clinical research on different immunotherapeutic approaches were highlighted, including immune checkpoint inhibitors, vaccines, immunomodulators, adoptive cell transfer and EBV‑specific monoclonal antibodies. The comprehensive overview of immunotherapy in NPC may provide insight for clinical practice and future investigation.
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Affiliation(s)
- Huageng Huang
- Department of Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong 510060
| | - Yuyi Yao
- Department of Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong 510060
| | - Xinyi Deng
- Department of Dermatology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120
| | - Zongyao Huang
- Department of Oncology, Senior Ward and Phase I Clinical Trial Ward, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China
| | - Yungchang Chen
- Department of Oncology, Senior Ward and Phase I Clinical Trial Ward, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China
| | - Zhao Wang
- Department of Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong 510060
| | - Huangming Hong
- Department of Oncology, Senior Ward and Phase I Clinical Trial Ward, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China
| | - He Huang
- Department of Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong 510060
| | - Tongyu Lin
- Department of Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong 510060
- Department of Oncology, Senior Ward and Phase I Clinical Trial Ward, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China
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16
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Jung M, Rose M, Knuechel R, Loeffler C, Muti H, Kather JN, Gaisa NT, on behalf of the German Study Group of Bladder Cancer (DFBK e.V.). Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer. BMC Cancer 2023; 23:113. [PMID: 36726072 PMCID: PMC9890720 DOI: 10.1186/s12885-023-10576-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 01/24/2023] [Indexed: 02/03/2023] Open
Abstract
AIMS Immune checkpoint inhibitor (ICI) therapy has become a viable treatment strategy in bladder cancer. However, treatment responses vary, and improved biomarkers are needed. Crucially, the characteristics of immune cells remain understudied especially in squamous differentiated bladder cancer (sq-BLCA). Here, we quantitatively analysed the tumour-immune phenotypes of sq-BLCA and correlated them with PD-L1 expression and FGFR3 mutation status. METHODS Tissue microarrays (TMA) of n = 68 non-schistosomiasis associated pure squamous cell carcinoma (SCC) and n = 46 mixed urothelial carcinoma with squamous differentiation (MIX) were subjected to immunohistochemistry for CD3, CD4, CD8, CD56, CD68, CD79A, CD163, Ki67, perforin and chloroacetate esterase staining. Quantitative image evaluation was performed via digital image analysis. RESULTS Immune infiltration was generally higher in stroma than in tumour regions. B-cells (CD79A) were almost exclusively found in stromal areas (sTILs), T-lymphocytes and macrophages were also present in tumour cell areas (iTILs), while natural killer cells (CD56) were nearly missing in any area. Tumour-immune phenotype distribution differed depending on the immune cell subset, however, hot tumour-immune phenotypes (high density of immune cells in tumour areas) were frequently found for CD8 + T-cells (33%), especially perforin + lymphocytes (52.2%), and CD68 + macrophages (37.6%). Perforin + CD8 lymphocytes predicted improved overall survival in sq-BLCA while high PD-L1 expression (CPS ≥ 10) was significantly associated with higher CD3 + , CD8 + and CD163 + immune cell density and high Ki67 (density) of tumour cells. Furthermore, PD-L1 expression was positively associated with CD3 + /CD4 + , CD3 + /CD8 + and CD68 + /CD163 + hot tumour-immune phenotypes. FGFR3 mutation status was inversely associated with CD8 + , perforin + and CD79A + lymphocyte density. CONCLUSIONS Computer-based image analysis is an efficient tool to analyse immune topographies in squamous bladder cancer. Hot tumour-immune phenotypes with strong PD-L1 expression might pose a promising subgroup for clinically successful ICI therapy in squamous bladder cancer and warrant further investigation.
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Affiliation(s)
- Max Jung
- grid.412301.50000 0000 8653 1507Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany ,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Michael Rose
- grid.412301.50000 0000 8653 1507Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany ,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Ruth Knuechel
- grid.412301.50000 0000 8653 1507Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany ,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
| | - Chiara Loeffler
- grid.412301.50000 0000 8653 1507Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany ,grid.4488.00000 0001 2111 7257Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Hannah Muti
- grid.412301.50000 0000 8653 1507Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany ,grid.4488.00000 0001 2111 7257Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Jakob Nikolas Kather
- grid.412301.50000 0000 8653 1507Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany ,grid.4488.00000 0001 2111 7257Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Nadine T. Gaisa
- grid.412301.50000 0000 8653 1507Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany ,Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany
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17
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Tang WC, Tsao SW, Jones GE, Liu X, Tsai MH, Delecluse HJ, Dai W, You C, Zhang J, Huang SCM, Leung MMH, Liu T, Ching YP, Chen H, Lo KW, Li X, Tsang CM. Latent membrane protein 1 and macrophage-derived TNFα synergistically activate and mobilize invadopodia to drive invasion of nasopharyngeal carcinoma. J Pathol 2023; 259:163-179. [PMID: 36420735 PMCID: PMC10108171 DOI: 10.1002/path.6036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 11/07/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
Invadopodia are actin-rich membrane protrusions that digest the matrix barrier during cancer metastasis. Since the discovery of invadopodia, they have been visualized as localized and dot-like structures in different types of cancer cells on top of a 2D matrix. In this investigation of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), a highly invasive cancer frequently accompanied by neck lymph node and distal organ metastases, we revealed a new form of invadopodium with mobilizing features. Integration of live-cell imaging and molecular assays revealed the interaction of macrophage-released TNFα and EBV-encoded latent membrane protein 1 (LMP1) in co-activating the EGFR/Src/ERK/cortactin and Cdc42/N-WASP signaling axes for mobilizing the invadopodia with lateral movements. This phenomenon endows the invadopodia with massive degradative power, visualized as a shift of focal dot-like digestion patterns on a 2D gelatin to a dendrite-like digestion pattern. Notably, single stimulation of either LMP1 or TNFα could only enhance the number of ordinary dot-like invadopodia, suggesting that the EBV infection sensitizes the NPC cells to form mobilizing invadopodia when encountering a TNFα-rich tumor microenvironment. This study unveils the interplay of EBV and stromal components in driving the invasive potential of NPC via unleashing the propulsion of invadopodia in overcoming matrix hurdles. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Wing Chung Tang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Sai Wah Tsao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Gareth E Jones
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK
| | - Xiong Liu
- Department of Otolaryngology - Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Ming Han Tsai
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | | | - Wei Dai
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Chanping You
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Jun Zhang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.,Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University, School of Medicine, Shenzhen, PR China
| | - Shaina Chor Mei Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Manton Man-Hon Leung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Tengfei Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Yick Pang Ching
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Honglin Chen
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Xin Li
- Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, PR China
| | - Chi Man Tsang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
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18
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Wang L, Wang D, Yang L, Zeng X, Zhang Q, Liu G, Pan Y. Cuproptosis related genes associated with Jab1 shapes tumor microenvironment and pharmacological profile in nasopharyngeal carcinoma. Front Immunol 2022; 13:989286. [PMID: 36618352 PMCID: PMC9816571 DOI: 10.3389/fimmu.2022.989286] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is the most common subcategory of head and neck squamous cell carcinoma (HNSCC). This study focused on the roles of cuproptosis related genes and Jab1 in the tumor microenvironment of NPC and HNSCC. METHODS Differential expression analysis of Jab1 and cuproptosis related genes in tumor cell enriched region (PanCK-expressing) and immune cell enriched region (CD45-expressing) of NPC microenvironment were performed by packages of R software. Survival analysis was performed using the survival and survminer packages. Corrplot package was used for correlation analysis. ConsensusClusterPlus package was used for cluster clustering among different regions of NPC, and functional enrichment analysis was performed using GSVA, GSEABase, clusterProfiler, org.Hs.eg.db and enrichplot packages. The pRRophetic package was used to predict drug sensitivity in NPC and HNSCC. RESULTS Relationships exist between cuproptosis related genes and Jab1 in the NPC microenvironment. The expression of cuproptosis related genes and Jab1 differed between tumor cell enriched region and immune cell enriched region. AKT inhibitor VIII, Doxorubicin, Bleomycin and Etoposide showed higher sensitivity to tumor cell than immune cell. In the high Jab1 group, higher expression of ATP7A, DBT, DLD and LIAS were associated with better prognosis of HNSCC patients. In contrast, in the low Jab1 group, higher expression of these genes is associated with worse prognosis of HNSCC patients. CONCLUSIONS Prognostic cuproptosis related genes and Jab1 provided a basis for targeted therapy and drug development.
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Affiliation(s)
- Liping Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Dujuan Wang
- Department of Clinical Pathology, Houjie Hospital of Dongguan, the Affiliated Houjie Hospital of Guangdong Medical University, Dongguan, China
| | - Liu Yang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Xiaojiao Zeng
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Qian Zhang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Guohong Liu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
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19
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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.
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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
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20
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Jiang J, Ying H. Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment. J Exp Clin Cancer Res 2022; 41:244. [PMID: 35964134 PMCID: PMC9375932 DOI: 10.1186/s13046-022-02457-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 01/13/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) arises from the epithelial cells located in the nasopharynx and has a distinct geographic distribution. Chronic Epstein-Barr virus (EBV) infection, as its most common causative agents, can be detected in 100% of NPC types. In-depth studies of the cellular and molecular events leading to immunosuppression in NPC have revealed new therapeutic targets and diverse combinations that promise to benefit patients with highly refractory, advanced and metastatic NPC. This paper reviews the mechanisms by which NPC cells to circumvent immune surveillance and approaches being attempted to restore immunity. We integrate existing insights into anti-NPC immunity and molecular signaling pathways as well as targeting therapies in anticipation of broader applicability and effectiveness in advanced metastatic NPC.
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21
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Lin JX, Lin JP, Weng Y, Lv CB, Chen JH, Zhan CY, Li P, Xie JW, Wang JB, Lu J, Chen QY, Cao LL, Lin M, Zhou WX, Zhang XJ, Zheng CH, Cai LS, Ma YB, Huang CM. Radiographical Evaluation of Tumor Immunosuppressive Microenvironment and Treatment Outcomes in Gastric Cancer: A Retrospective, Multicohort Study. Ann Surg Oncol 2022; 29:5022-5033. [PMID: 35532827 DOI: 10.1245/s10434-022-11499-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/05/2022] [Indexed: 11/18/2022]
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22
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Jin YN, Liu BQ, Peng KW, Ou XQ, Zeng WS, Zhang WJ, Marks T, Yao JJ, Xia LP. The prognostic value of adding systemic inflammation response index to Epstein-Barr virus DNA in childhood nasopharyngeal carcinoma: A real-world study. Head Neck 2022; 44:1404-1413. [PMID: 35373866 DOI: 10.1002/hed.27033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/28/2022] [Accepted: 03/09/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND To assess the prognostic value of the systemic inflammation response index (SIRI) combined with plasma load of Epstein-Barr virus (EBV) DNA in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC). METHODS A total of 205 consecutive patients with CALANPC were enrolled. We used recursive partitioning analysis (RPA) to classify patients into various risk groups, with a primary endpoint of overall survival (OS). RESULTS Elevated SIRI (≥1.53) and EBV DNA (≥4000 copy/ml) were significantly associated with inferior OS in CALANPC. RPA categorized patients into low- and high-risk groups based on prognostic factors. Survival curves showed excellent discrimination in OS (95.3% vs 77.6%; p < 0.001) between the low- and high-risk groups. A significant improvement was confirmed using the prognostic methods for conventional TNM staging systems (p < 0.05). CONCLUSIONS The combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination in CALANPC.
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Affiliation(s)
- Ya-Nan Jin
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
- The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Biomedical Imaging, Zhuhai, Guangdong Province, China
| | - Bao-Qiu Liu
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Kun-Wei Peng
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Xue-Qing Ou
- The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Biomedical Imaging, Zhuhai, Guangdong Province, China
| | - Wu-Shuang Zeng
- The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Biomedical Imaging, Zhuhai, Guangdong Province, China
| | - Wang-Jian Zhang
- Department of Medical Statistics, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Tia Marks
- Department of Environmental Health Sciences, School of Public Health, University at Albany, State University of New York, Rensselaer, New York, USA
| | - Ji-Jin Yao
- The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Biomedical Imaging, Zhuhai, Guangdong Province, China
| | - Liang-Ping Xia
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
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23
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Proteomic profiling of exosomes in a mouse model of Candida albicans endophthalmitis. Exp Cell Res 2022; 417:113222. [PMID: 35618014 DOI: 10.1016/j.yexcr.2022.113222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 11/21/2022]
Abstract
Exosomes play pivotal roles in intercellular communication, and pathophysiological functions. In this study, we aimed to understand the role of exosomal proteome derived from C. albicans infected mice (C57BL/6) eyeball. Exosomes were characterized by Dynamic Light Scattering and western blot, quantified and subjected to LC-MS/MS and cytokine quantification by ELISA. The average size of exosomes was 170-200 nm with number of exosomes amounted to 1.42 × 1010 in infected set compared to control (1.24 × 109). Western blot was positive for CD9, CD63 and CD81 confirming the presence of exosomes. IL-6, IL1β, TNF-α, and IFN-γ levels were significantly elevated in infected eye at 72 h.p.i. Proteomic analysis identified 42 differentially expressed proteins, of these 37 were upregulated and 5 were downregulated. Gene Ontology (GO) revealed enrichment of cell adhesion, cytoskeleton organization, and cellular response proteins such as aquaporin-5, gasdermin-A, CD5 antigen-like, Catenin, V-ATPase, and vesicle associated protein. Additionally, KEGG pathway analysis indicated the association of metabolic and carbon signalling pathways with exosomes from C. albicans infected eye. The protein cargo in exosomes released during endophthalmitis with C. albicans seems to play a unique role in the pathogenesis of the disease and further validations with larger cohort of patients is required to confirm them as biomarkers. .
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24
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Lisovska N. Multilevel mechanism of immune checkpoint inhibitor action in solid tumors: History, present issues and future development (Review). Oncol Lett 2022; 23:190. [PMID: 35527781 PMCID: PMC9073577 DOI: 10.3892/ol.2022.13310] [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: 01/19/2022] [Accepted: 03/31/2022] [Indexed: 11/12/2022] Open
Abstract
Immunotherapy with checkpoint inhibitors (antibodies that target and block immune checkpoints in the tumor microenvironment) is included in the standard of care for patients with different types of malignancy, such as melanoma, renal cell and urothelial carcinoma, lung cancer etc. The introduction of this new immunotherapy has altered the view on potential targets for treatment of solid tumors from tumor cells themselves to their immune microenvironment; this has led to a reconsideration of the mechanisms of tumor-associated immunity. However, only a subset of patients benefit from immunotherapy and patient response is often unpredictable, even with known initial levels of prognostic markers; the biomarkers for favorable response are still being investigated. Mechanisms of immune checkpoint inhibitors efficiency, as well as the origins of treatment failure, require further investigation. From a clinical standpoint, discrepancies between the theoretical explanation of inhibitors of immune checkpoint actions at the cellular level and their deployment at a tissue/organ level impede the effective clinical implementation of novel immune therapy. The present review assessed existing experimental and clinical data on functional activity of inhibitors of immune checkpoints to provide a more comprehensive picture of their mechanisms of action on a cellular and higher levels of biological organization.
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Affiliation(s)
- Natalya Lisovska
- Chemotherapy Department, Center of Oncology, ‘Cyber Clinic of Spizhenko’, Kapitanovka, Kyiv 08112, Ukraine
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25
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Wang Y, Sun Q, Ye Y, Sun X, Xie S, Zhan Y, Song J, Fan X, Zhang B, Yang M, Lv L, Hosaka K, Yang Y, Nie G. FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis. JCI Insight 2022; 7:157874. [PMID: 35439170 PMCID: PMC9220856 DOI: 10.1172/jci.insight.157874] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/15/2022] [Indexed: 12/24/2022] Open
Abstract
Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalks among various cell compartments in supporting metastasis remain poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here we report an elevation of FGF-2 signaling in both nasopharyngeal carcinoma (NPC) patient samples and xenograft mouse models promotes NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1- AHR signaling. Gain and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization towards an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposomes treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2-FGFR1-pericyte-CXCL14-TAM stromal communication axis in NPC and propose an effective anti-metastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2-high tumors.
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Affiliation(s)
- Yujie Wang
- Department of Otolaryngology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Qi Sun
- Fudan University, Shanghai, China
| | - Ying Ye
- Department of Oral Implantology, Tongji University, Shanghai, China
| | - Xiaoting Sun
- Department of Cellular and Genetic Medicine, Fudan University, Shanghai, China
| | - Sisi Xie
- Department of Cellular and Genetic Medicine, Fudan University, Shanghai, China
| | - Yuhang Zhan
- Department of Cellular and Genetic Medicine, Fudan University, Shanghai, China
| | - Jian Song
- Department of Otolaryngology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Xiaoqin Fan
- Department of Otolaryngology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Bin Zhang
- Department of Otolaryngology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Ming Yang
- Department of Otolaryngology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Lei Lv
- Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China
| | - Kayoko Hosaka
- Department of Microbiology, Karolinska Institute, Stockholm, Sweden
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, Fudan University, Shanghai, China
| | - Guohui Nie
- Department of Otolaryngology, Shenzhen Second People's Hospital, Shenzhen, China
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26
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Su ZY, Siak PY, Leong CO, Cheah SC. Nasopharyngeal Carcinoma and Its Microenvironment: Past, Current, and Future Perspectives. Front Oncol 2022; 12:840467. [PMID: 35311066 PMCID: PMC8924466 DOI: 10.3389/fonc.2022.840467] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/11/2022] [Indexed: 12/31/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy that raises public health concerns in endemic countries. Despite breakthroughs in therapeutic strategies, late diagnosis and drug resistance often lead to unsatisfactory clinical outcomes in NPC patients. The tumor microenvironment (TME) is a complex niche consisting of tumor-associated cells, such as fibroblasts, endothelial cells, leukocytes, that influences tumor initiation, progression, invasion, and metastasis. Cells in the TME communicate through various mechanisms, of note, exosomes, ligand-receptor interactions, cytokines and chemokines are active players in the construction of TME, characterized by an abundance of immune infiltrates with suppressed immune activities. The NPC microenvironment serves as a target-rich niche for the discovery of potential promising predictive or diagnostic biomarkers and the development of therapeutic strategies. Thus, huge efforts have been made to exploit the role of the NPC microenvironment. The whole picture of the NPC microenvironment remains to be portrayed to understand the mechanisms underlying tumor biology and implement research into clinical practice. The current review discusses the recent insights into the role of TME in the development and progression of NPC which results in different clinical outcomes of patients. Clinical interventions with the use of TME components as potential biomarkers or therapeutic targets, their challenges, and future perspectives will be introduced. This review anticipates to provide insights to the researchers for future preclinical, translational and clinical research on the NPC microenvironment.
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Affiliation(s)
- Zhi Yi Su
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Pui Yan Siak
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Chee-Onn Leong
- Centre of Cancer and Stem Cells Research, International Medical University, Kuala Lumpur, Malaysia
- Institute for Research, Development and Innovation, International Medical University, Kuala Lumpur, Malaysia
| | - Shiau-Chuen Cheah
- Faculty of Medicine and Health Sciences, UCSI University, Kuala Lumpur, Malaysia
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27
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Human glutathione peroxidase codon 198 variant increases nasopharyngeal carcinoma risk and progression. Eur Arch Otorhinolaryngol 2021; 278:4027-4034. [PMID: 33616746 DOI: 10.1007/s00405-021-06628-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/16/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Glutathione peroxidase 1 (GPx-1) is a selenium-dependent detoxifying enzyme involved in the protection of cells against oxidative damage. Some genetic association studies reported significant associations between GPx-1 Pro198Leu variant and carcinogenesis across different populations; however, the impact of this variant on nasopharyngeal carcinoma (NPC) has not been explored. Therefore, the present study was planned to evaluate the potential involvement of the GPx-1 Pro198Leu variant and plasma GPx activity in the risk of developing NPC in a Tunisian population. METHODS The GPx-1 Pro198Leu genotype was determined in 327 NPC patients and 150 healthy controls by the RFLP-PCR analysis. The correlation between the GPx-1 variant and the clinicopathological parameters was examined. GPx activity was assessed in the plasma of 119 NPC patients and 58 healthy control subjects and according to GPx-1 genotypes and clinicopathological characteristics of NPC patients. RESULTS A significant association was found between GPx-1 Pro198Leu variant and NPC risk in a Tunisian population. The allelic frequencies of Pro and Leu alleles were 32% versus 68% and 41% versus 59% in NPC cases and controls, respectively. Thus, the minor 198 Leu allele increased significantly in NPC patients and appeared as a potential risk factor for NPC occurrence (OR = 1.48, CI 95% = 1.14-1.91, p = 0.002). The plasma GPx activity was significantly higher in NPC patients than in controls (p = 0.03). According to the clinicopathological characteristics of NPC patients, GPx activity decreased significantly in patients with lymph node metastasis (p = 0.004). CONCLUSION This is the first study showing a strong association between GPx-1 Pro198Leu genetic variant and NPC risk. GPx-1 Pro198Leu variant increased the development of regional lymph node metastasis. Plasma GPx activity was higher in NPC patients. Thus, GPx-1 gene could be considered as a determinant factor influencing NPC risk and progression.
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28
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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.
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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
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29
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Huang H, Li S, Tang Q, Zhu G. Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma. Front Immunol 2021; 12:680955. [PMID: 34566954 PMCID: PMC8458828 DOI: 10.3389/fimmu.2021.680955] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/25/2021] [Indexed: 01/31/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx mainly characterized by geographic distribution and EBV infection. Metabolic reprogramming, one of the cancer hallmarks, has been frequently reported in NPCs to adapt to internal energy demands and external environmental pressures. Inevitably, the metabolic reprogramming within the tumor cell will lead to a decreased pH value and diverse nutritional supplements in the tumor-infiltrating micro-environment incorporating immune cells, fibroblasts, and endothelial cells. Accumulated evidence indicates that metabolic reprogramming derived from NPC cells may facilitate cancer progression and immunosuppression by cell-cell communications with their surrounding immune cells. This review presents the dysregulated metabolism processes, including glucose, fatty acid, amino acid, nucleotide metabolism, and their mutual interactions in NPC. Moreover, the potential connections between reprogrammed metabolism, tumor immunity, and associated therapy would be discussed in this review. Accordingly, the development of targets on the interactions between metabolic reprogramming and immune cells may provide assistances to overcome the current treatment resistance in NPC patients.
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Affiliation(s)
- Huimei Huang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shisheng Li
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qinglai Tang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Gangcai Zhu
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
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30
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Peng RR, Liang ZG, Chen KH, Li L, Qu S, Zhu XD. Nomogram Based on Lactate Dehydrogenase-to-Albumin Ratio (LAR) and Platelet-to-Lymphocyte Ratio (PLR) for Predicting Survival in Nasopharyngeal Carcinoma. J Inflamm Res 2021; 14:4019-4033. [PMID: 34447260 PMCID: PMC8385134 DOI: 10.2147/jir.s322475] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/28/2021] [Indexed: 12/29/2022] Open
Abstract
Purpose The prognosis of inflammation-related indicators like lactate dehydrogenase/albumin ratio (LAR) and the platelet/lymphocyte ratio (PLR) in nasopharyngeal carcinoma (NPC) is not yet clear. Our objective is to establish and verify the nomogram using LAR and PLR ratio for the first time to explore the prognostic value in NPC. Patients and Methods This was a retrospective collection of 1661 patients with non-metastatic NPC admitted to our hospital from 2010 to 2017. The final variables of overall survival (OS) and progression-free survival (PFS) were selected by Cox regression analysis to establish nomograms, and the methods to verify the prediction precision and discriminative ability of the nomograms were concordance index (C index), the receiver operating characteristic (ROC) curve and calibration curve. The risk stratification was carried out through the nomograms and compared with the current staging system by the Kaplan–Meier methods. Results Multivariate Cox analysis resulted that age, plasma Epstein–Barr Virus (EBV) DNA, T stage, N stage, white blood cells (WBC), PLR and LAR were independent prognostic risk factors for OS and PFS, and sex is an independent prognostic risk factor for OS. The C-indexes of OS nomogram were 0.722 (95% CI: 0.706–0.738) and 0.747 (95% CI: 0.717–0.777) in the training cohort and validation cohort, which were statistically higher than the current 8th AJCC staging system (0.646 and 0.688). The C-indexes of PFS nomogram were 0.696 (95% CI: 0.680–0.713) and 0.690 (95% CI: 0.660–0.720), which were also statistically higher than the current 8th AJCC staging system (0.632 and 0.666). Otherwise, ROC curves and the calibration curve for probability also confirmed satisfied consistency with actual observations. Conclusion LAR is a novel useful independent factor in NPC. The proposed nomogram LAR and PLR resulted in more accurate prognostic prediction than current staging system for NPC patients.
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Affiliation(s)
- Ru-Rong Peng
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Zhong-Guo Liang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Kai-Hua Chen
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Ling Li
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Song Qu
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China
| | - Xiao-Dong Zhu
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People's Republic of China.,Department of Oncology, Affiliated Wu-Ming Hospital of Guangxi Medical University, Nanning, People's Republic of China
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31
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Luo H, Yi B. The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application. Int J Biol Sci 2021; 17:2147-2156. [PMID: 34239345 PMCID: PMC8241729 DOI: 10.7150/ijbs.59688] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022] Open
Abstract
Exosomes are nanoscale membrane vesicles, which carry biologically active substances of their cell of origin and play an important role in signal transduction and intercellular communication. At present, exosomes have been identified as a promising non-invasive liquid biopsy biomarker in the tissues and circulating blood of nasopharyngeal carcinoma (NPC) and found to participate in regulating pathophysiological process of the tumor. We here review recent insights gained into the molecular mechanisms of exosome-induced cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance and chemotherapy resistance in the development and progression of NPC, as well as the clinical application of exosomes as diagnostic biomarkers and therapeutic agents. We also discuss the limitations and challenges in exosome application. We hope this review may provide some references for the use of exosomes in clinical intervention.
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Affiliation(s)
- Huidan Luo
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Bin Yi
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
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32
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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.
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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
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33
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Liu Y, He S, Wang XL, Peng W, Chen QY, Chi DM, Chen JR, Han BW, Lin GW, Li YQ, Wang QY, Peng RJ, Wei PP, Guo X, Li B, Xia X, Mai HQ, Hu XD, Zhang Z, Zeng YX, Bei JX. Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution. Nat Commun 2021; 12:741. [PMID: 33531485 PMCID: PMC7854640 DOI: 10.1038/s41467-021-21043-4] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
The heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8+ T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8+ T and immune-suppressive TNFRSF4+ Treg cells in tumours might derive from peripheral CX3CR1+CD8+ T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3+ DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3+ DCs, Treg, exhausted CD8+ T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.
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Affiliation(s)
- Yang Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Shuai He
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, People's Republic of China
- Center for Precision Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Xi-Liang Wang
- BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, 100871, People's Republic of China
| | - Wan Peng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Qiu-Yan Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Dong-Mei Chi
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
- Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Jie-Rong Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
- Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China
| | - Bo-Wei Han
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Guo-Wang Lin
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Yi-Qi Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Qian-Yu Wang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Rou-Jun Peng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Pan-Pan Wei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Xiang Guo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Bo Li
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
- RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China
| | - Xiaojun Xia
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Hai-Qiang Mai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China
| | - Xue-Da Hu
- BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, 100871, People's Republic of China
| | - Zemin Zhang
- BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, 100871, People's Republic of China.
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, People's Republic of China.
| | - Yi-Xin Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China.
| | - Jin-Xin Bei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China.
- The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, People's Republic of China.
- Center for Precision Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
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34
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Cao Y, Xie L, Shi F, Tang M, Li Y, Hu J, Zhao L, Zhao L, Yu X, Luo X, Liao W, Bode AM. Targeting the signaling in Epstein-Barr virus-associated diseases: mechanism, regulation, and clinical study. Signal Transduct Target Ther 2021; 6:15. [PMID: 33436584 PMCID: PMC7801793 DOI: 10.1038/s41392-020-00376-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/30/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022] Open
Abstract
Epstein–Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.
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Affiliation(s)
- Ya Cao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China. .,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China. .,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China. .,Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, 410078, Changsha, China. .,Molecular Imaging Research Center of Central South University, 410008, Changsha, Hunan, China. .,National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, 410078, Changsha, China. .,Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.
| | - Longlong Xie
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Feng Shi
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Min Tang
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China.,Molecular Imaging Research Center of Central South University, 410008, Changsha, Hunan, China
| | - Yueshuo Li
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Jianmin Hu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Lin Zhao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Luqing Zhao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China
| | - Xinfang Yu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China.,Molecular Imaging Research Center of Central South University, 410008, Changsha, Hunan, China
| | - Weihua Liao
- Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
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35
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Zou Z, Ha Y, Liu S, Huang B. Identification of tumor-infiltrating immune cells and microenvironment-relevant genes in nasopharyngeal carcinoma based on gene expression profiling. Life Sci 2020; 263:118620. [PMID: 33096113 DOI: 10.1016/j.lfs.2020.118620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/30/2020] [Accepted: 10/11/2020] [Indexed: 12/24/2022]
Abstract
AIMS The purpose of this study was to investigate the prognostic significance of tumor-infiltrating immune cells and microenvironment-relevant genes in nasopharyngeal carcinoma (NPC) and their correlations. MATERIALS AND METHODS The "xCell" algorithm was used to calculate the enrichment scores for 33 immune cells in the samples of GSE12452, GSE40290, GSE53819, GSE68799, and GSE102349. The difference of immune cells between NPC group and non-cancerous group and the prognostic value of the immune cells were analyzed. Besides, based on the Microenvironment scores, the differentially expressed genes (DEGs) between the high- and low-score groups were screened to identify the microenvironment-relevant hub genes. Furthermore, the DEGs were used to establish a risk score model for predicting progression-free survival (PFS) via LASSO penalized Cox regression. KEY FINDINGS The scores of B-cells and Memory B-cells of NPC were significantly lower than those of non-cancerous tissues, and they were positively associated with PFS. Moreover, 10 hub genes (PTPRC, CD19, CD79B, BTK, CD79A, SELL, MS4A1, CD38, CD52, and CD22) were identified and positively correlated with B-cells, Memory B-cells, and Microenvironment scores in GSE12452, GSE68799, and GSE102349. High expression levels of CD22, CD38, CD79B, MS4A1, SELL, and PTPRC were associated with longer PFS. Besides, a risk score model composed of DARC, IL33, IGHG1, and SLC6A8 was established with a good performance for PFS prediction. SIGNIFICANCE These results enhance our understanding of the composition and prognostic significance of tumor-infiltrating immune cells in NPC lesions, and provide potential targets for prognostication and immunotherapy for NPC patients.
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Affiliation(s)
- Zhenning Zou
- Department of Pathology, Guangdong Medical University, Zhanjiang, China
| | - Yanping Ha
- Department of Pathology, Guangdong Medical University, Zhanjiang, China
| | - Shuguang Liu
- Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Bowan Huang
- Department of Anesthesiology, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China.
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36
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Cheng K, Zhang RY, Yang XQ, Zhang XS, Zhang F, An J, Wang ZY, Dong Y, Liu B, Zhao YD, Liu TC. One-for-All Nanoplatform for Synergistic Mild Cascade-Potentiated Ultrasound Therapy Induced with Targeting Imaging-Guided Photothermal Therapy. ACS APPLIED MATERIALS & INTERFACES 2020; 12:40052-40066. [PMID: 32806885 DOI: 10.1021/acsami.0c10475] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Ameliorated therapy based on the tumor microenvironment is becoming increasingly popular, yet only a few methods have achieved wide recognition. Herein, targeting multifunctional hydrophilic nanomicelles, AgBiS2@DSPE-PEG2000-FA (ABS-FA), were obtained and employed for tumor treatment. In a cascade amplification mode, ABS-FA exhibited favorable properties of actively enhancing computed tomography/infrared (CT/IR) imaging and gently relieving ambient oxygen concentration by cooperative photothermal and sonodynamic therapy. Compared with traditional Bi2S3 nanoparticles, the CT imaging capability of the probe was augmented (43.21%), and the photothermal conversion efficiency was increased (33.1%). Furthermore, remarkable ultrasonic dynamic features of ABS-FA were observed, with increased generation of reactive oxygen species (24.3%) being obtained compared to Ce6, a commonly used sonosensitizer. Furthermore, ABS-FA exhibited obvious inhibitory effects on HeLa cell migration at 6 μg/mL, which to some extent, demonstrated its suppressive effect on tumor growth. A lower dose, laser and ultrasonic power, and shorter processing time endowed ABS-FA with excellent photothermal and sonodynamic effects. By mild cascade mode, the hypoxic condition of the tumor site was largely improved, and a suitable oxygen-rich environment was provided, thereby endowing ABS-FA with a superior synergistically enhanced treatment effect compared with the single-mode approach, which ultimately realized the purpose of "one injection, multiple treatment". Moreover, our data showed that ABS-FA was given with a biological safety profile while harnessing in vivo. Taken together, as a synergistically enhanced medical diagnosis and treatment method, the one-for-all nanoplatform will pave a new avenue for further clinical applications.
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Affiliation(s)
- Kai Cheng
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Ruo-Yun Zhang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Xiao-Quan Yang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
- Key Laboratory of Biomedical Photonics (HUST), Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Xiao-Shuai Zhang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Fang Zhang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Jie An
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Zhuo-Ya Wang
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Ying Dong
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, Guangdong, P. R. China
| | - Bo Liu
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Yuan-Di Zhao
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
- Key Laboratory of Biomedical Photonics (HUST), Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Tian-Cai Liu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, Guangdong, P. R. China
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37
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Zhang CX, Huang DJ, Baloche V, Zhang L, Xu JX, Li BW, Zhao XR, He J, Mai HQ, Chen QY, Zhang XS, Busson P, Cui J, Li J. Galectin-9 promotes a suppressive microenvironment in human cancer by enhancing STING degradation. Oncogenesis 2020; 9:65. [PMID: 32632113 PMCID: PMC7338349 DOI: 10.1038/s41389-020-00248-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/11/2020] [Accepted: 06/16/2020] [Indexed: 12/13/2022] Open
Abstract
Galectin-9 (Gal-9) is known to enhance the expansion of myeloid-derived suppressor cells (MDSCs) in murine models. Its contribution to the expansion of MDSCs in human malignancies remain to be investigated. We here report that Gal-9 expression in nasopharyngeal carcinoma (NPC) cells enhances the generation of MDSCs (CD33+CD11b+HLA-DR−) from CD33+ bystander cells. The underlying mechanisms involve both the intracellular and secreted Gal-9. Inside carcinoma cells, Gal-9 up-regulates the expression of a variety of pro-inflammatory cytokines which are critical for MDSC differentiation, including IL-1β and IL-6. This effect is mediated by accelerated STING protein degradation resulting from direct interaction of the Gal-9 carbohydrate recognition domain 1 with the STING C-terminus and subsequent enhancement of the E3 ubiquitin ligase TRIM29-mediated K48-linked ubiquitination of STING. Moreover, we showed that extracellular Gal-9 secreted by carcinoma cells can enter the myeloid cells and trigger the same signaling cascade. Consistently, high concentrations of tumor and plasma Gal-9 are associated with shortened survival of NPC patients. Our findings unearth that Gal-9 induces myeloid lineage-mediated immunosuppression in tumor microenvironments by suppressing STING signaling.
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Affiliation(s)
- Chuan-Xia Zhang
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.,MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Sun Yat-sen University, 510275, Guangzhou, China
| | - Dai-Jia Huang
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Valentin Baloche
- CNRS, UMR 9018, Gustave Roussy and Université Paris-Saclay 39 rue Camille Desmoulins, F-94805, Villejuif, France
| | - Lin Zhang
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China
| | - Jing-Xiao Xu
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China
| | - Bo-Wen Li
- Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, 213000, Jiangsu, China
| | - Xin-Rui Zhao
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Sun Yat-sen University, 510275, Guangzhou, China
| | - Jia He
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.,MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Sun Yat-sen University, 510275, Guangzhou, China
| | - Hai-Qiang Mai
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Qiu-Yan Chen
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Xiao-Shi Zhang
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.,Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China
| | - Pierre Busson
- CNRS, UMR 9018, Gustave Roussy and Université Paris-Saclay 39 rue Camille Desmoulins, F-94805, Villejuif, France.
| | - Jun Cui
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China. .,MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, Sun Yat-sen University, 510275, Guangzhou, China. .,Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen International Biological Valley-Life Science Industrial Park, Dapeng New District, Shenzhen, China.
| | - Jiang Li
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, and School of Life Sciences, Sun Yat-sen University, 510060, Guangzhou, P. R. China.
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Chu YL, Li H, Ng PLA, Kong ST, Zhang H, Lin Y, Tai WCS, Yu ACS, Yim AKY, Tsang HF, Cho WCS, Wong SCC. The potential of circulating exosomal RNA biomarkers in cancer. Expert Rev Mol Diagn 2020; 20:665-678. [PMID: 32188269 DOI: 10.1080/14737159.2020.1745064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 03/17/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION There are great potentials of using exosomal RNAs (exoRNA) as biomarkers in cancers. The isolation of exoRNA requires the use of ultracentrifugation to isolate cell-free RNA followed by detection using real-time PCR, microarray, next-generation sequencing, or Nanostring nCounter system. The use of exoRNA enrichment panels has largely increased the detection sensitivity and specificity when compared to traditional diagnostic tests. Moreover, using exoRNA as biomarkers can assist the early detection of chemo and radioresistance cancer, and in turn opens up the possibility of personalized treatment to patients. Finally, exoRNA can be detected at an early stage of cancer recurrence to improve the survival rate. AREAS COVERED In this review, the authors summarized the detection methods of exoRNA as well as its potential as a biomarker in cancer diagnosis and chemo and radioresistance. EXPERT OPINION The application of exoRNAs in clinical diagnosis is still in its infancy. Further researches on extracellular vesicles isolation, detection protocols, exoRNA classes and subclasses, and the regulatory biological pathways have to be performed before exoRNA can be applied translationally.
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Affiliation(s)
- Yin Lam Chu
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Harriet Li
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Pik Lan Amanda Ng
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Siu Ting Kong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Hao Zhang
- Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College , Guangzhou, Guangdong, China
| | - Yusheng Lin
- Department of Immunotherapy and Gastrointestinal Oncology, Affiliated Cancer Hospital of Shantou University Medical College , Shantou, Guangdong, China
| | - William Chi Shing Tai
- Department of Applied Biology and Chemical Technology, Faculty of Applied Sciences and Textiles, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region , Kowloon, China
| | | | | | - Hin Fung Tsang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | | | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
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Novel Therapies Boosting T Cell Immunity in Epstein Barr Virus-Associated Nasopharyngeal Carcinoma. Int J Mol Sci 2020; 21:ijms21124292. [PMID: 32560253 PMCID: PMC7352617 DOI: 10.3390/ijms21124292] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/05/2020] [Accepted: 06/12/2020] [Indexed: 12/11/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumour of the head and neck affecting localised regions of the world, with the highest rates described in Southeast Asia, Northern Africa, and Greenland. Its high morbidity rate is linked to both late-stage diagnosis and unresponsiveness to conventional anti-cancer treatments. Multiple aetiological factors have been described including environmental factors, genetics, and viral factors (Epstein Barr Virus, EBV), making NPC treatment that much more complex. The most common forms of NPCs are those that originate from the epithelial tissue lining the nasopharynx and are often linked to EBV infection. Indeed, they represent 75–95% of NPCs in the low-risk populations and almost 100% of NPCs in high-risk populations. Although conventional surgery has been improved with nasopharyngectomy’s being carried out using more sophisticated surgical equipment for better tumour resection, recent findings in the tumour microenvironment have led to novel treatment options including immunotherapies and photodynamic therapy, able to target the tumour and improve the immune system. This review provides an update on the disease’s aetiology and the future of NPC treatments with a focus on therapies activating T cell immunity.
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Baloche V, Ferrand FR, Makowska A, Even C, Kontny U, Busson P. Emerging therapeutic targets for nasopharyngeal carcinoma: opportunities and challenges. Expert Opin Ther Targets 2020; 24:545-558. [PMID: 32249657 DOI: 10.1080/14728222.2020.1751820] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
Introduction: Nasopharyngeal carcinoma (NPC) is a major public health problem in several countries, especially those in Southeast Asia and North Africa. In its typical poorly differentiated form, the Epstein-Barr virus (EBV) genome is present in the nuclei of all malignant cells with restricted expression of a few viral genes. The malignant phenotype of NPC cells results from the influence of these viral products in combination with cellular genetic, epigenetic and functional alterations. With regard to host/tumor interactions, NPC is a remarkable example of immune escape in the context of a hot tumor.Areas covered: This article has an emphasis on emerging therapeutic targets that are considered upstream or at an early stage of clinical application. It examines targets related to cellular oncogenic alterations, latent EBV infection and tumor interactions with the immune system.Expert opinion: There is a remarkable emergence of new agents that target EBV products. The clinical application of these agents would benefit from a systematic and comprehensive molecular classification of NPCs and from easy access to pre-clinical models in public repositories. There is a strong rationale for more investigations on the potential of immune modulators, especially those related to NK cells.
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Affiliation(s)
- Valentin Baloche
- CNRS, UMR 9018, Gustave Roussy and Uuniversité Paris-Saclay, 39, rue Camille Desmoulins, Villejuif, France
| | | | - Anna Makowska
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Caroline Even
- Département de cancérologie cervico-faciale, Gustave Roussy and université Paris-Saclay, 39, rue Camille Desmoulins, F-94805, Villejuif, France
| | - Udo Kontny
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Pierre Busson
- CNRS, UMR 9018, Gustave Roussy and Uuniversité Paris-Saclay, 39, rue Camille Desmoulins, Villejuif, France
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Klatka J, Hymos A, Szkatuła-Łupina A, Grywalska E, Klatka B, Terpiłowski M, Stepulak A. T-Lymphocyte Activation Is Correlated With the Presence of Anti-EBV in Patients With Laryngeal Squamous Cell Carcinoma. In Vivo 2020; 33:2007-2012. [PMID: 31662531 DOI: 10.21873/invivo.11697] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 07/25/2019] [Accepted: 07/30/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND/AIM Chronic viral infection is an important risk factor in the development of cancer. Failure of immune response to clear the oncogenic infection can facilitate cancer progression. The aim of the present study was to analyze early and late activation of T-lymphocytes related to Epstein-Barr virus (EBV) infection by the expression of markers of activation (CD69, CD25) on the surface of T-lymphocytes (CD3+, CD4+, CD8+) in patients bearing laryngeal cancer according to absence/presence immunoglobulin G antibodies to EBV nuclear antigen (EBNA1). MATERIALS AND METHODS Thirty-three patients with laryngeal squamous cell carcinoma (LC) and 20 volunteers without cancer (control group) were enrolled in the study. Peripheral blood samples were collected from every individual. The markers of activation of T-lymphocytes were determined by flow cytometry, whereas commercial immunoenzymatic assay kits were used for detection of anti-viral capsid antigen (VCA) IgM, anti-VCA IgG, and anti-EBNA1 IgG. RESULTS Increased early activation of CD8+ and CD4+ T-lymphocytes was found in patients with LC. There was a significantly higher proportion of CD4+ and CD8+T-lymphocytes expressing CD69 antigen in patients with LC compared to the control group. The proportion of CD4+ CD25+ T-lymphocytes in patients with LC positive for anti-EBNA1 IgG and anti-VCA IgM was lower compared to patients without antibodies to VCA IgM. CONCLUSION The dysfunction of immune response in larynx cancer patients could be associated with EBV infection.
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Affiliation(s)
- Janusz Klatka
- Department of Otolaryngology and Laryngeal Oncology, Medical University of Lublin, Lublin, Poland
| | - Anna Hymos
- Department of Otolaryngology and Laryngeal Oncology, Medical University of Lublin, Lublin, Poland
| | - Anna Szkatuła-Łupina
- Department of Otolaryngology and Laryngeal Oncology, Medical University of Lublin, Lublin, Poland
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Lublin, Poland
| | - Barbara Klatka
- Department of Otolaryngology and Laryngeal Oncology, Medical University of Lublin, Lublin, Poland
| | - Michał Terpiłowski
- Department of Otolaryngology and Laryngeal Oncology, Medical University of Lublin, Lublin, Poland
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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Lu T, Chen Y, Li J, Guo Q, Lin W, Zheng Y, Su Y, Zong J, Lin S, Ye Y, Pan J. High Soluble Programmed Death-Ligand 1 Predicts Poor Prognosis in Patients with Nasopharyngeal Carcinoma. Onco Targets Ther 2020; 13:1757-1765. [PMID: 32161471 PMCID: PMC7051865 DOI: 10.2147/ott.s242517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose Immune checkpoint proteins in the tumor microenvironment can enter the blood circulation and are potential markers for liquid biopsy. The aims of this study were to explore differences in immune checkpoint protein expression between patients with nasopharyngeal carcinoma (NPC) and healthy controls and to investigate the prognostic value of the soluble form of programmed death-ligand 1 (sPD-L1) in NPC. Methods In total, 242 patients were included in the disease group. Plasma samples from 23 NPC patients and 15 healthy control were used for immune checkpoint protein panel assays. Samples from 219 patients with NPC including 30 paired pre-treatment and post-radiotherapy samples were evaluated by enzyme-linked immunosorbent assay to determine sPD-L1 levels. Results A total of 14 immune checkpoint proteins, including sPD-L1were upregulated in 23 patients with NPC (all p<0.001) compared with 15 healthy controls. Among 219 patients, the median follow-up time was 50 months (7–82 months). Based on the optimal cutoff value of 93.7 pg/mL, patients with high expression of sPD-L1 had worse distant metastasis-free survival (87.5% vs 74.0%, p=0.006) than those of patients with low expression. Multivariate analysis showed that sPD-L1 (HR=1.99, p=0.048) and EBV-DNA (HR=2.51, p=0.030) were poor prognostic factors for DMFS. In the group with high EBV-DNA expression, DMFS was worse for patients with high sPD-L1 expression than those with low sPD-L1 expression (56.4% vs 82.6%, p=0.002). Conclusion Plasma immune checkpoint protein expression differed significantly between patients with NPC and healthy donors. Plasma sPD-L1 levels are a candidate prognostic biomarker, especially when combined with EBV-DNA.
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Affiliation(s)
- Tianzhu Lu
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, People's Republic of China
| | - Yiping Chen
- Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Jieyu Li
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital, Fuzhou, People's Republic of China
| | - Qiaojuan Guo
- Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Wansong Lin
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital, Fuzhou, People's Republic of China
| | - Yuhong Zheng
- Department of Clinical Laboratory, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Ying Su
- Department of Radiation Biology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Jingfeng Zong
- Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Shaojun Lin
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, People's Republic of China.,Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Yunbin Ye
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital, Fuzhou, People's Republic of China.,The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People's Republic of China
| | - Jianji Pan
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, People's Republic of China.,Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People's Republic of China
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Development and validation of an immune checkpoint-based signature to predict prognosis in nasopharyngeal carcinoma using computational pathology analysis. J Immunother Cancer 2019; 7:298. [PMID: 31722750 PMCID: PMC6854706 DOI: 10.1186/s40425-019-0752-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 09/20/2019] [Indexed: 12/30/2022] Open
Abstract
Background Immunotherapy, especially immune checkpoint inhibition, has provided powerful tools against cancer. We aimed to detect the expression of common immune checkpoints and evaluate their prognostic values in nasopharyngeal carcinoma (NPC). Methods The expression of 9 immune checkpoints consistent with 13 features was detected in the training cohort (n = 208) by immunohistochemistry and quantified by computational pathology. Then, the LASSO cox regression model was used to construct an immune checkpoint-based signature (ICS), which was validated in a validation cohort containing 125 patients. Results High positive expression of PD-L1 and B7-H4 was observed in tumour cells (TCs), whereas PD-L1, B7-H3, B7-H4, IDO-1, VISTA, ICOS and OX40 were highly expressed in tumour-associated immune cells (TAICs). Eight of the 13 immune features were associated with patient overall survival, and an ICS classifier consisting of 5 features (B7-H3TAIC, IDO-1TAIC, VISTATAIC, ICOSTAIC, and LAG3TAIC) was established. Patients with high-risk scores in the training cohort had shorter overall (P < 0.001), disease-free (P = 0.002), and distant metastasis-free survival (P = 0.004), which were confirmed in the validation cohort. Multivariate analysis revealed that the ICS classifier was an independent prognostic factor. A combination of the ICS classifier and TNM stage had better prognostic value than the TNM stage alone. In addition, the ICS classifier was significantly associated with survivals in patients with high EBV-DNA load. Conclusions We determined the expression status of nine immune checkpoints consistent with 13 features in NPC and further constructed an ICS prognostic model, which might add prognostic value to the TNM staging system.
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Tsang CM, Lui VWY, Bruce JP, Pugh TJ, Lo KW. Translational genomics of nasopharyngeal cancer. Semin Cancer Biol 2019; 61:84-100. [PMID: 31521748 DOI: 10.1016/j.semcancer.2019.09.006] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/11/2019] [Accepted: 09/11/2019] [Indexed: 12/26/2022]
Abstract
Nasopharyngeal carcinoma (NPC), also named the Cantonese cancer, is a unique cancer with strong etiological association with infection of the Epstein-Barr virus (EBV). With particularly high prevalence in Southeast Asia, the involvement of EBV and genetic aberrations contributive to NPC tumorigenesis have remained unclear for decades. Recently, genomic analysis of NPC has defined it as a genetically homogeneous cancer, driven largely by NF-κB signaling caused by either somatic aberrations of NF-κB negative regulators or by overexpression of the latent membrane protein 1 (LMP1), an EBV viral oncoprotein. This represents a landmark finding of the NPC genome. Exome and RNA sequencing data from new EBV-positive NPC models also highlight the importance of PI3K pathway aberrations in NPC. We also realize for the first time that NPC mutational burden, mutational signatures, MAPK/PI3K aberrations, and MHC Class I gene aberrations, are prognostic for patient outcome. Together, these multiple genomic discoveries begin to shape the focus of NPC therapy development. Given the challenge of NF-κB targeting in human cancers, more innovative drug discovery approaches should be explored to target the unique atypical NF-κB activation feature of NPC. Our next decade of NPC research should focus on further identification of the -omic landscapes of recurrent and metastatic NPC, development of gene-based precision medicines, as well as large-scale drug screening with the newly developed and well-characterized EBV-positive NPC models. Focused preclinical and clinical investigations on these major directions may identify new and effective targeting strategies to further improve survival of NPC patients.
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Affiliation(s)
- Chi Man Tsang
- Department of Anatomical and cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Vivian Wai Yan Lui
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Jeffrey P Bruce
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Trevor J Pugh
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON, M5G 1L7, Canada
| | - Kwok Wai Lo
- Department of Anatomical and cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
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Vitha AE, Kollefrath AW, Huang CYC, Garcia-Godoy F. Characterization and Therapeutic Uses of Exosomes: A New Potential Tool in Orthopedics. Stem Cells Dev 2019; 28:141-150. [DOI: 10.1089/scd.2018.0205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
| | | | | | - Franklin Garcia-Godoy
- Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, Tennessee
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Tan LSY, Wong B, Gangodu NR, Lee AZE, Kian Fong Liou A, Loh KS, Li H, Yann Lim M, Salazar AM, Lim CM. Enhancing the immune stimulatory effects of cetuximab therapy through TLR3 signalling in Epstein-Barr virus (EBV) positive nasopharyngeal carcinoma. Oncoimmunology 2018; 7:e1500109. [PMID: 30377565 DOI: 10.1080/2162402x.2018.1500109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/05/2018] [Accepted: 07/07/2018] [Indexed: 10/28/2022] Open
Abstract
Cetuximab immunotherapy targeting the epidermal growth factor receptor (EGFR) has been used to treat nasopharyngeal cancer (NPC) with some success. Therefore, combining an immune adjuvant to boost the immune microenvironment may improve its clinical efficacy. Herein, we investigate the immune-stimulatory effects of Poly-ICLC (a TLR3 agonist) in enhancing cetuximab-based immunotherapy and correlate these responses with FcɣRIIIa (V158F) or TLR3 single nucleotide polymorphisms (SNPs- L412F and C829T) expressed on immune effector cells. We observed high levels of TLR3 mRNA in NPC cells; and both TLR3 and EGFR expression were unaffected by Poly-ICLC treatment. Cetuximab plus Poly-ICLC significantly enhanced NK-mediated ADCC through up-regulation of CD107a and Granzyme B expression. This effect was independent of FcɣRIIIa-V158F and TLR3-L412F or TLR3-C829T polymorphisms expressed on NK cells. Additionally, IFN-ɣ expression and secretion were doubled following cetuximab plus poly-ICLC treatment; compared to either treatment alone. This effect was independent of TLR3 polymorphisms. Consequentially, adaptive immune responses were also seen with increased DC maturation (CD83), co-stimulatory molecules expression (CD80 and CD86) and increased frequency of EGFR-specific CD8 + T cells following Poly-ICLC treatment. The percentage of CD80+ CD83+ and CD83+ CD86+ DC was highest in the Poly-ICLC plus cetuximab group, compared to either treatment alone. These results demonstrate the effectiveness of Poly-ICLC in enhancing both cetuximab-mediated innate and adaptive anti-tumor immunity against NPC, which is independent of FcɣRIIIa-158, TLR3-L412F or TLR3-C829T polymorphisms. Additionally, Poly-ICLC does not downregulate EGFR expression on NPC cells and hence, will not dampen cetuximab anti-tumor activity.
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Affiliation(s)
- Louise Soo Yee Tan
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Benjamin Wong
- Department of Pathology, National University Health System Singapore, Singapore
| | - Nagaraja Rao Gangodu
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Andrea Zhe Ern Lee
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Anthony Kian Fong Liou
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Kwok Seng Loh
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Hao Li
- Department of Otorhinolaryngology, Tan Tock Seng Hospital, Singapore
| | - Ming Yann Lim
- Department of Otorhinolaryngology, Tan Tock Seng Hospital, Singapore
| | | | - Chwee Ming Lim
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore.,Department of Otolaryngology, National University of Singapore, Singapore
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Camargo MC, Sivins A, Isajevs S, Folkmanis V, Rudzīte D, Gulley ML, Offerhaus GJ, Leja M, Rabkin CS. Associations of Epstein-Barr Virus-Positive Gastric Adenocarcinoma with Circulating Mediators of Inflammation and Immune Response. Cancers (Basel) 2018; 10:cancers10090284. [PMID: 30142953 PMCID: PMC6162799 DOI: 10.3390/cancers10090284] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 08/16/2018] [Accepted: 08/20/2018] [Indexed: 12/30/2022] Open
Abstract
Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. Our study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status. From a Latvian series of 302 gastric cancer cases, we measured plasma levels of 92 immune-related proteins in the 28 patients with EBV-positive tumors and 34 patients with EBV-negative tumors. Eight markers were statistically significantly higher with tumor EBV positivity: chemokine C-C motif ligand (CCL) 20 (Odds Ratio (OR) = 3.6; p-trend = 0.001), chemokine C-X-C motif ligand 9 (OR = 3.6; p-trend = 0.003), programmed death-ligand 1 (PD-L1; OR = 3.4; p-trend = 0.004), interleukin (IL)-10 (OR = 2.4; p-trend = 0.019), CCL19 (OR = 2.3; p-trend = 0.019), CCL11 (OR = 2.2; p-trend = 0.026), IL-17A (OR = 2.0; p-trend = 0.038) and CCL8 (OR = 1.9; p-trend = 0.049). Systemic responses to EBV-positive gastric cancer are characterized by alterations in chemokines and PD-L1. Profiling of these molecules may enable non-invasive diagnosis of EBV status when tumor tissue is unavailable. Our findings provide theoretical justification for clinical evaluations of immune checkpoint therapy for EBV-positive gastric cancer.
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Affiliation(s)
- M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr., BG 9609/6E338, Bethesda, MD 20892, USA.
| | - Armands Sivins
- Institute of Clinical and Preventive Medicine and Faculty of Medicine, University of Latvia, LV1586 Riga, Latvia.
| | - Sergejs Isajevs
- Institute of Clinical and Preventive Medicine and Faculty of Medicine, University of Latvia, LV1586 Riga, Latvia.
| | - Valdis Folkmanis
- Institute of Clinical and Preventive Medicine and Faculty of Medicine, University of Latvia, LV1586 Riga, Latvia.
| | - Dace Rudzīte
- Institute of Clinical and Preventive Medicine and Faculty of Medicine, University of Latvia, LV1586 Riga, Latvia.
| | - Margaret L Gulley
- Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
| | - G Johan Offerhaus
- Department of Pathology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
| | - Marcis Leja
- Institute of Clinical and Preventive Medicine and Faculty of Medicine, University of Latvia, LV1586 Riga, Latvia.
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr., BG 9609/6E338, Bethesda, MD 20892, USA.
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Chen Y, Jiang W, Xi D, Chen J, Xu G, Yin W, Chen J, Gu W. Development and validation of nomogram based on SIRI for predicting the clinical outcome in patients with nasopharyngeal carcinomas. J Investig Med 2018; 67:691-698. [PMID: 30127099 PMCID: PMC6581120 DOI: 10.1136/jim-2018-000801] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2018] [Indexed: 12/26/2022]
Abstract
The Systemic Inflammation Response Index (SIRI), based on peripheral lymphocyte, neutrophil, and monocyte counts, was recently investigated as a prognostic marker for several tumors. However, use of the SIRI has not been reported for nasopharyngeal carcinoma (NPC). We evaluated the prognostic value of the SIRI in primary and validation cohorts. We also established an effective prognostic nomogram for NPC based on clinicopathological parameters and the SIRI. The predictive accuracy and discriminative ability of the nomogram were determined using the concordance index (C-index) and a calibration curve and were compared with tumor-node-metastasis classifications. Our Kaplan-Meier survival analysis results showed that the SIRI was associated with the overall survival of patients with NPC in the primary and validation cohorts. The SIRI was identified to be an independent prognostic factor for NPC. In addition, we developed and validated a new prognostic nomogram that integrated clinicopathological factors and the SIRI. This nomogram can efficiently predict the prognosis of patients with NPC. The SIRI is a novel, simple and inexpensive prognostic predictor for patients with NPC. The SIRI has important value for predicting the prognosis of patients with NPC and developing individualized treatment plans.
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Affiliation(s)
- Yuan Chen
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wenjie Jiang
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dan Xi
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jun Chen
- Department of Respiratory, The Seventh People's Hospital of Changzhou, Changzhou, China
| | - Guoping Xu
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wenming Yin
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Junjun Chen
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wendong Gu
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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Tsao SW, Tsang CM, Lo KW. Epstein-Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0270. [PMID: 28893937 DOI: 10.1098/rstb.2016.0270] [Citation(s) in RCA: 409] [Impact Index Per Article: 58.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2017] [Indexed: 12/24/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.This article is part of the themed issue 'Human oncogenic viruses'.
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Affiliation(s)
- Sai Wah Tsao
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Chi Man Tsang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology and State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
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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.
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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.
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