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Lee SH, Khoo ASB, Griffiths JR, Mat Lazim N. Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus. Int J Cancer 2025; 156:488-498. [PMID: 39291683 DOI: 10.1002/ijc.35192] [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: 07/15/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.
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Affiliation(s)
- Shen-Han Lee
- Department of Otorhinolaryngology-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Alan Soo-Beng Khoo
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
- Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - John R Griffiths
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Norhafiza Mat Lazim
- Department of Otorhinolaryngology-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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McMiller TL, Besharati S, Yarchoan M, Zhu Q, Ünsal-Kaçmaz K, Xu K, Lee J, Bhaijee F, Engle LL, Taube JM, Berger AE, Anders RA, Topalian SL. Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy. J Immunother Cancer 2024; 12:e010201. [PMID: 39572160 PMCID: PMC11580252 DOI: 10.1136/jitc-2024-010201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Gastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5-10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(-) GCs. METHODS Over 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(-)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes. RESULTS IHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(-) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1. In contrast, EBV(-) tumors overexpressed several functionally-related gene groups associated with myeloid cells (CD163, IL1A, NOS2, RIGI), immunosuppressive cytokines/chemokines (CXCL2, CXCR4, IL10, IL32), coinhibitory molecules (HAVCR2/TIM-3 and VSIR/VISTA), and adenosine pathway components (ENTPD1/ CD39 and NT5E/CD73). Notably, compared with EBV+ GCs, EBV(-) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(-) versus EBV+ GCs (p=0.068). CONCLUSIONS While certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(-) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(-) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
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Affiliation(s)
- Tracee L McMiller
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sepideh Besharati
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Qingfeng Zhu
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Ke Xu
- Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Junghwa Lee
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Feriyl Bhaijee
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Logan L Engle
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Janis M Taube
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan E Berger
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Robert A Anders
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Suzanne L Topalian
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Bos J, Groen-van Schooten TS, Brugman CP, Jamaludin FS, van Laarhoven HWM, Derks S. The tumor immune composition of mismatch repair deficient and Epstein-Barr virus-positive gastric cancer: A systematic review. Cancer Treat Rev 2024; 127:102737. [PMID: 38669788 DOI: 10.1016/j.ctrv.2024.102737] [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: 02/13/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. METHODS A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. RESULTS In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. DISCUSSION AND CONCLUSION MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.
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Affiliation(s)
- J Bos
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - T S Groen-van Schooten
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - C P Brugman
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - F S Jamaludin
- Amsterdam UMC Location University of Amsterdam, Medical Library AMC, Meibergdreef 9, Amsterdam, the Netherlands
| | - H W M van Laarhoven
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - S Derks
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands.
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Yee EJ, Gilbert D, Kaplan J, van Dyk L, Kim SS, Berg L, Clambey E, Wani S, McCarter MD, Stewart CL. Immune Landscape of Epstein-Barr Virus-Associated Gastric Cancer: Analysis From a Western Academic Institution. J Surg Res 2024; 296:742-750. [PMID: 38368775 PMCID: PMC10947842 DOI: 10.1016/j.jss.2024.01.043] [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: 10/17/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/20/2024]
Abstract
INTRODUCTION Epstein-Barr virus-associated gastric cancer (EBVaGC) may be a meaningful biomarker for potential benefit from immunotherapy. Further investigation is needed to characterize the immune landscape of EBVaGC. We assessed our institutional frequency of surgically treated EBVaGC and analyzed the immunologic biomarker profile and tumor-infiltrating lymphocyte (TIL) phenotypes of a series of EBVaGC compared to non-EBVaGC cases. METHODS Available tissue samples from all patients with biopsy-confirmed gastric adenocarcinoma who underwent resection with curative intent from 2012 to 2020 at our institution were collected. In situ hybridization was used to assess EBV status; multiplex immunohistochemistry was performed to assess mismatch repair status, Programmed Death-Ligand 1 (PD-L1) expression, and phenotypic characterization of TILs. RESULTS Sixty-eight samples were included in this study. EBVaGC was present in 3/68 (4%) patients. Among all patients, 27/68 (40%) had positive PD-L1 expression; two of three (67%) EBVaGC patients exhibited positive PD-L1 expression. Compared to non-EBVaGC, EBV-positive tumors showed 5-fold to 10-fold higher density of TILs in both tumor and stroma and substantially elevated CD8+ T cell to Tregulatory cell ratio. The memory subtypes of CD8+ and CD4+ T cells were upregulated in EBVaGC tumors and stromal tissue compared to non-EBVaGC. CONCLUSIONS The incidence of surgically resected EBVaGC at our center was 4%. EBVaGC tumors harbor elevated levels of TILs, including memory subtypes, within both tumor and tumor-related stroma. Robust TIL presence and upregulated PD-L1 positivity in EBVaGC may portend promising responses to immunotherapy agents. Further investigation into routine EBV testing and TIL phenotype of patients with gastric cancer to predict response to immunotherapy may be warranted.
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Affiliation(s)
- Elliott J Yee
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, Colorado.
| | | | - Jeffrey Kaplan
- Department of Pathology, University of Colorado, Aurora, Colorado
| | - Linda van Dyk
- Department of Immunology & Microbiology, University of Colorado, Aurora, Colorado
| | - Sunnie S Kim
- Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO
| | - Leslie Berg
- Department of Immunology & Microbiology, University of Colorado, Aurora, Colorado
| | - Eric Clambey
- Department of Anesthesiology, University of Colorado, Aurora, Colorado
| | - Sachin Wani
- Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO
| | - Martin D McCarter
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, Colorado
| | - Camille L Stewart
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Aurora, Colorado
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Salnikov MY, MacNeil KM, Mymryk JS. The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape. Front Immunol 2024; 15:1358511. [PMID: 38596668 PMCID: PMC11002251 DOI: 10.3389/fimmu.2024.1358511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/14/2024] [Indexed: 04/11/2024] Open
Abstract
Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an "immune-hot" phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.
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Affiliation(s)
- Mikhail Y. Salnikov
- Department of Microbiology and Immunology, Western University, London, ON, Canada
| | - Katelyn M. MacNeil
- Department of Microbiology and Immunology, Western University, London, ON, Canada
| | - Joe S. Mymryk
- Department of Microbiology and Immunology, Western University, London, ON, Canada
- Department of Oncology, Western University, London, ON, Canada
- Department of Otolaryngology, Western University, London, ON, Canada
- Lawson Health Research Institute, London, ON, Canada
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Amarillo ME, Moyano A, Ferressini Gerpe N, De Matteo E, Preciado MV, Chabay P. Tonsillar cytotoxic CD4 T cells are involved in the control of EBV primary infection in children. Sci Rep 2024; 14:2135. [PMID: 38273012 PMCID: PMC10810912 DOI: 10.1038/s41598-024-52666-4] [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: 11/10/2023] [Accepted: 01/22/2024] [Indexed: 01/27/2024] Open
Abstract
CD4 T cells play a key role in Epstein Barr virus (EBV) infection, by modulating latent antigen expression, and exhibiting cytotoxic and regulatory properties. Our aim was to evaluate the presence of Granzyme B (GZMB) and Foxp3 CD4 T cells at different EBV infection status and latency profiles. We examined CD4, GZMB, Foxp3, IL10, TGF-β, CD4-GZMB and CD4-Foxp3 expression at the tonsils of pediatric patients with different infective status and EBV latency profiles. CD4+, GZMB+, Foxp3+, CD4-GZMB+ and CD4-Foxp3+ cell counts were higher at the interfollicular region. Higher expression of CD4-GZMB was found in primary infected patients compared to healthy carriers. In patients that expressed latency III antigens, we demonstrated lower CD4+, CD4-GZMB+, CD4-Foxp3+ expression; a negative correlation between the immunoregulatory cytokine IL-10+ and GZMB+ as well as a positive correlation of IL-10+ and CD4+. In patients expressing the lytic protein BMRF1, a positive correlation of TGF-β+ with CD4-GZMB+ and CD4-Foxp3+ was observed. Our findings indicate that CD4-GZMB+ cells are involved in the restriction of primary EBV infection in pediatric patients, which could partially explain the lack of symptoms, whereas both CD4-GZMB+ and CD4-Foxp3+ cells could be involved in the modulation of latency.
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Affiliation(s)
- María Eugenia Amarillo
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina
| | - Agustina Moyano
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina
| | - Natalia Ferressini Gerpe
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina
| | - Elena De Matteo
- Pathology Division, Ricardo Gutierrez Children's Hospital, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina
| | - Maria Victoria Preciado
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina
| | - Paola Chabay
- Molecular Biology Laboratory, Pathology Division, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutierrez Children's Hospital, Gallo 1330, C1425EFD, Ciudad Autónoma de Buenos Aires, Argentina.
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Huang X, Zhang M, Zhang Z. The Role of LMP1 in Epstein-Barr Virus-associated Gastric Cancer. Curr Cancer Drug Targets 2024; 24:127-141. [PMID: 37183458 DOI: 10.2174/1568009623666230512153741] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 05/16/2023]
Abstract
EBV promotes many cancers such as lymphoma, nasopharyngeal carcinoma, and gastric; Latent Membrane Protein 1 (LMP1) is considered to be a major oncogenic protein encoded by Epstein- Barr virus (EBV). LMP1 functions as a carcinogen in lymphoma and nasopharyngeal carcinoma, and LMP1 may also promote gastric cancer. The expression level of LMP1 in host cells is a key determinant in tumorigenesis and maintenance of virus specificity. By promoting cell immortalization and cell transformation, promoting cell proliferation, affecting immunity, and regulating cell apoptosis, LMP1 plays a crucial tumorigenic role in epithelial cancers. However, very little is currently known about LMP1 in Epstein-Barr virus-associated gastric cancer (EBVaGC); the main reason is that the expression level of LMP1 in EBVaGC is comparatively lower than other EBV-encoded proteins, such as The Latent Membrane Protein 2A (LMP2A), Epstein-Barr nuclear antigen 1 (EBNA1) and BamHI-A rightward frame 1 (BARF1), to date, there are few studies related to LMP1 in EBVaGC. Recent studies have demonstrated that LMP1 promotes EBVaGC by affecting The phosphatidylinositol 3-kinase- Akt (PI3K-Akt), Nuclear factor-kappa B (NF-κB), and other signaling pathways to regulate many downstream targets such as Forkhead box class O (FOXO), C-X-C-motif chemokine receptor (CXCR), COX-2 (Cyclooxygenase-2); moreover, the gene methylation induced by LMP1 in EBVaGC has become one of the characteristics that distinguish this gastric cancer (GC) from other types of gastric cancer and LMP1 also promotes the formation of the tumor microenvironment (TME) of EBVaGC in several ways. This review synthesizes previous relevant literature, aiming to highlight the latest findings on the mechanism of action of LMP1 in EBVaGC, summarize the function of LMP1 in EBVaGC, lay the theoretical foundation for subsequent new research on LMP1 in EBVaGC, and contribute to the development of novel LMP1-targeted drugs.
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Affiliation(s)
- Xinqi Huang
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Meilan Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiwei Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
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Ulase D, Behrens HM, Krüger S, Heckl SM, Ebert U, Becker T, Röcken C. LAG3 in gastric cancer: it's complicated. J Cancer Res Clin Oncol 2023; 149:10797-10811. [PMID: 37311986 PMCID: PMC10423140 DOI: 10.1007/s00432-023-04954-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023]
Abstract
PURPOSE Lymphocyte activation gene 3 (LAG3) is thought to contribute to T cell exhaustion within the tumor microenvironment of solid tumors. This study aimed to analyze the spatial distribution of LAG3 + cells in relation to clinicopathological and survival data in a large set of 580 primary resected and neoadjuvantly treated gastric cancers (GC). METHODS LAG3 expression was evaluated in tumor center and invasive margin using immunohistochemistry and whole-slide digital image analysis. Cases were divided into LAG3-low and LAG3-high expression groups based on (1) median LAG3 + cell density, (2) cut-off values adapted to cancer-specific survival using Cutoff Finder application. RESULTS Significant differences in spatial distribution of LAG3 + cells were observed in primarily resected GC, but not in neoadjuvantly treated GC. LAG3 + cell density showed evident prognostic value at following cut-offs: in primarily resected GC, 21.45 cells/mm2 in tumor center (17.9 vs. 10.1 months, p = 0.008) and 208.50 cells/mm2 in invasive margin (33.8 vs. 14.7 months, p = 0.006); and in neoadjuvantly treated GC, 12.62 cells/mm2 (27.3 vs. 13.2 months, p = 0.003) and 123.00 cells/mm2 (28.0 vs. 22.4 months, p = 0.136), respectively. Significant associations were found between LAG3 + cell distribution patterns and various clinicopathological factors in both cohorts. In neoadjuvantly treated GC, LAG3 + immune cell density was found to be an independent prognostic factor of survival (HR = 0.312, 95% CI 0.162-0.599, p < 0.001). CONCLUSION In this study, a higher density of LAG3 + cells was associated with favorable prognosis. Current results support the need for extended analysis of LAG3. Differences in the distribution of LAG3 + cells should be considered, as they could influence clinical outcomes and treatment responses.
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Affiliation(s)
- Dita Ulase
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Hans-Michael Behrens
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Steffen M. Heckl
- Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Ulrike Ebert
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
| | - Thomas Becker
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105 Kiel, Germany
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9
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Liu S, Deng Z, Zhu J, Ma Z, Tuo B, Li T, Liu X. Gastric immune homeostasis imbalance: An important factor in the development of gastric mucosal diseases. Biomed Pharmacother 2023; 161:114338. [PMID: 36905807 DOI: 10.1016/j.biopha.2023.114338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/18/2023] [Accepted: 01/27/2023] [Indexed: 03/11/2023] Open
Abstract
The gastric mucosal immune system is a unique immune organ independent of systemic immunity that not only maintains nutrient absorption but also plays a role in resisting the external environment. Gastric mucosal immune disorder leads to a series of gastric mucosal diseases, including autoimmune gastritis (AIG)-related diseases, Helicobacter pylori (H. pylori)-induced diseases, and various types of gastric cancer (GC). Therefore, understanding the role of gastric mucosal immune homeostasis in gastric mucosal protection and the relationship between mucosal immunity and gastric mucosal diseases is very important. This review focuses on the protective effect of gastric mucosal immune homeostasis on the gastric mucosa, as well as multiple gastric mucosal diseases caused by gastric immune disorders. We hope to offer new prospects for the prevention and treatment of gastric mucosal diseases.
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Affiliation(s)
- Shuhui Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zilin Deng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Jiaxing Zhu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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10
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Salnikov M, Prusinkiewicz MA, Lin S, Ghasemi F, Cecchini MJ, Mymryk JS. Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion. Viruses 2023; 15:176. [PMID: 36680216 PMCID: PMC9860965 DOI: 10.3390/v15010176] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/01/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.
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Affiliation(s)
- Mikhail Salnikov
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
| | - Martin A Prusinkiewicz
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
| | - Sherman Lin
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
| | - Farhad Ghasemi
- Department of General Surgery, Western University, London, ON N6A 3K7, Canada
| | - Matthew J Cecchini
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Otolaryngology, Western University, London, ON N6A 5W9, Canada
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11
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Zhou H, Jing S, Liu Y, Wang X, Duan X, Xiong W, Li R, Peng Y, Ai Y, Fu D, Wang H, Zhu Y, Zeng Z, He Y, Ye Q. Identifying the key genes of Epstein-Barr virus-regulated tumour immune microenvironment of gastric carcinomas. Cell Prolif 2022; 56:e13373. [PMID: 36519208 PMCID: PMC9977676 DOI: 10.1111/cpr.13373] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 12/23/2022] Open
Abstract
The Epstein-Barr virus (EBV) is involved in the carcinogenesis of gastric cancer (GC) upon infection of normal cell and induces a highly variable composition of the tumour microenvironment (TME). However, systematic bioinformatics analysis of key genes associated with EBV regulation of immune infiltration is still lacking. In the present study, the TCGA and GEO databases were recruited to analyse the association between EBV infection and the profile of immune infiltration in GC. The weighted gene co-expression analysis (WGCNA) was applied to shed light on the key gene modules associated with EBV-associated immune infiltration in GC. 204 GC tissues were used to analysed the expression of key hub genes by using the immunohistochemical method. Real-time PCR was used to evaluate the association between the expression of EBV latent/lytic genes and key immune infiltration genes. Our results suggested that EBV infection changed the TME of GC mainly regulates the TIICs. The top three hub genes of blue (GBP1, IRF1, and LAP3) and brown (BIN2, ITGAL, and LILRB1) modules as representative genes were associated with EBV infection and GC immune infiltration. Furthermore, EBV-encoded LMP1 expression is account for the overexpression of GBP1 and IRF1. EBV infection significantly changes the TME of GC, and the activation of key immune genes was more dependent on the invasiveness of the whole EBV virion instead of single EBV latent/lytic gene expression.
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Affiliation(s)
- Heng Zhou
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Shuili Jing
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yu Liu
- College of Life and Health Sciences, Institute of Biology and MedicineWuhan University of Science and TechnologyWuhanHubeiChina
| | - Xuming Wang
- Department of PathologyGuilin Medical UniversityGuilinGuangxiChina
| | - Xingxiang Duan
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Wei Xiong
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Ruohan Li
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Youjian Peng
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yilong Ai
- Foshan Hospital of Stomatology, School of Medicine, Foshan UniversityFoshanGuangdongChina
| | - Dehao Fu
- Department of Orthopaedics, Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hui Wang
- Demonstration Center for Experimental Basic Medicine Education, Wuhan UniversityWuhanChina
| | - Yaoqi Zhu
- Institute of Regenerative and Translational MedicineTianyou Hospital of Wuhan University of Science and TechnologyWuhanHubeiChina,Department of oral and maxillofacial surgeryHospital of Taikang Tongji (Wuhan)WuhanChina
| | - Zhi Zeng
- Department of PathologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yan He
- Institute of Regenerative and Translational MedicineTianyou Hospital of Wuhan University of Science and TechnologyWuhanHubeiChina,Department of oral and maxillofacial surgery, Massachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Qingsong Ye
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina,Department of oral and maxillofacial surgery, Massachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
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12
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Atri-Schuller A, Abushukair H, Cavalcante L, Hentzen S, Saeed A, Saeed A. Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer. Curr Issues Mol Biol 2022; 44:5756-5767. [PMID: 36421674 PMCID: PMC9689242 DOI: 10.3390/cimb44110390] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 09/30/2023] Open
Abstract
Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of Indoleamine 2,3-Dioxygenase 1 (IDO1), synergism between H. pylori and EBV co-infection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.
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Affiliation(s)
- Aviva Atri-Schuller
- Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45219, USA
| | - Hassan Abushukair
- Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Ludimila Cavalcante
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
| | - Stijn Hentzen
- Department of Internal Medicine, Kansas University Medical Center, Kansas City, KS 66160, USA
| | - Azhar Saeed
- Department of Pathology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, University of Kansas Cancer Center, 2330 Shawnee Mission Pkwy, Kansas City, KS 66205, USA
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13
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Deep learning model to predict Epstein-Barr virus associated gastric cancer in histology. Sci Rep 2022; 12:18466. [PMID: 36323712 PMCID: PMC9630260 DOI: 10.1038/s41598-022-22731-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 10/18/2022] [Indexed: 11/20/2022] Open
Abstract
The detection of Epstein-Barr virus (EBV) in gastric cancer patients is crucial for clinical decision making, as it is related with specific treatment responses and prognoses. Despite its importance, the limited medical resources preclude universal EBV testing. Herein, we propose a deep learning-based EBV prediction method from H&E-stained whole-slide images (WSI). Our model was developed using 319 H&E stained WSI (26 EBV positive; TCGA dataset) from the Cancer Genome Atlas, and 108 WSI (8 EBV positive; ISH dataset) from an independent institution. Our deep learning model, EBVNet consists of two sequential components: a tumor classifier and an EBV classifier. We visualized the learned representation by the classifiers using UMAP. We externally validated the model using 60 additional WSI (7 being EBV positive; HGH dataset). We compared the model's performance with those of four pathologists. EBVNet achieved an AUPRC of 0.65, whereas the four pathologists yielded a mean AUPRC of 0.41. Moreover, EBVNet achieved an negative predictive value, sensitivity, specificity, precision, and F1-score of 0.98, 0.86, 0.92, 0.60, and 0.71, respectively. Our proposed model is expected to contribute to prescreen patients for confirmatory testing, potentially to save test-related cost and labor.
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14
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Kim HN, Ahn S, Kim KM. Gastric cancer with Epstein-Barr virus heterogeneity: Evaluation of the frequency, clinicopathologic features, and genomic profiles. Pathol Res Pract 2022; 238:154108. [PMID: 36126450 DOI: 10.1016/j.prp.2022.154108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/27/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P = 0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles.
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Affiliation(s)
- Han-Na Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soomin Ahn
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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15
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Zhang JY, Du Y, Gong LP, Shao YT, Wen JY, Sun LP, He D, Guo JR, Chen JN, Shao CK. EBV-Induced CXCL8 Upregulation Promotes Vasculogenic Mimicry in Gastric Carcinoma via NF-κB Signaling. Front Cell Infect Microbiol 2022; 12:780416. [PMID: 35321317 PMCID: PMC8936189 DOI: 10.3389/fcimb.2022.780416] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/09/2022] [Indexed: 12/26/2022] Open
Abstract
Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC via NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.
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Affiliation(s)
- Jing-yue Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Du
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li-ping Gong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yi-ting Shao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Jing-yun Wen
- Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li-ping Sun
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dan He
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jin-rui Guo
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian-ning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Jian-ning Chen, ; Chun-kui Shao,
| | - Chun-kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Jian-ning Chen, ; Chun-kui Shao,
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16
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Bai Y, Xie T, Wang Z, Tong S, Zhao X, Zhao F, Cai J, Wei X, Peng Z, Shen L. Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer. J Immunother Cancer 2022; 10:jitc-2021-004080. [PMID: 35241494 PMCID: PMC8896035 DOI: 10.1136/jitc-2021-004080] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2022] [Indexed: 12/14/2022] Open
Abstract
Background Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is a distinct molecular subtype of GC with a favorable prognosis. However, the exact effects and potential mechanisms of EBV infection on immune checkpoint blockade (ICB) efficacy in GC remain to be clarified. Additionally, EBV-encoded RNA (EBER) in situ hybridization (ISH), the traditional method to detect EBV, could cause false-positive/false-negative results and not allow for characterizing other molecular biomarkers recommended by standard treatment guidelines for GC. Herein, we sought to investigate the efficacy and potential biomarkers of ICB in EBVaGC identified by next-generation sequencing (NGS). Design An NGS-based algorithm for detecting EBV was established and validated using two independent GC cohorts (124 in the training cohort and 76 in the validation cohort). The value of EBV infection for predicting ICB efficacy was evaluated among 95 patients with advanced or metastatic GC receiving ICB. The molecular predictive biomarkers for ICB efficacy were identified to improve the prediction accuracy of ICB efficacy in 22 patients with EBVaGC. Results Compared with orthogonal assay (EBER-ISH) results, the NGS-based algorithm achieved high performance with a sensitivity of 95.7% (22/23) and a specificity of 100% (53/53). EBV status was identified as an independent predictive factor for overall survival and progression-free survival in patients with DNA mismatch repair proficient (pMMR) GC following ICB. Moreover, the patients with EBV+/pMMR and EBV−/MMR deficient (dMMR) had comparable and favorable survival following ICB. Twenty-two patients with EBV+/pMMR achieved an objective response rate of 54.5% (12/22) on immunotherapy. Patients with EBVaGC with a high cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) level were less responsive to anti-programmed death-1/ligand 1 (PD-1/L1) monotherapy, and the combination of anti-CTLA-4 plus anti-PD-1/L1 checkpoint blockade benefited patients with EBVaGC more than anti-PD-1/L1 monotherapy with a trend close to significance (p=0.074). There were nearly significant differences in tumor mutational burden (TMB) level and SMARCA4 mutation frequency between the ICB response and non-response group. Conclusions We developed an efficient NGS-based EBV detection strategy, and this strategy-identified EBV infection was as effective as dMMR in predicting ICB efficacy in GC. Additionally, we identified CTLA-4, TMB, and SMARCA4 mutation as potential predictive biomarkers of ICB efficacy in EBVaGC, which might better inform ICB treatment for EBVaGC.
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Affiliation(s)
- Yuezong Bai
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Tong Xie
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Shuang Tong
- Medical Affairs, 3D Medicines, Inc, Shanghai, China
| | | | - Feilong Zhao
- Medical Affairs, 3D Medicines, Inc, Shanghai, China
| | - Jinping Cai
- Medical Affairs, 3D Medicines, Inc, Shanghai, China
| | - Xiaofan Wei
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
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17
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Chakravorty S, Afzali B, Kazemian M. EBV-associated diseases: Current therapeutics and emerging technologies. Front Immunol 2022; 13:1059133. [PMID: 36389670 PMCID: PMC9647127 DOI: 10.3389/fimmu.2022.1059133] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/13/2022] Open
Abstract
EBV is a prevalent virus, infecting >90% of the world's population. This is an oncogenic virus that causes ~200,000 cancer-related deaths annually. It is, in addition, a significant contributor to the burden of autoimmune diseases. Thus, EBV represents a significant public health burden. Upon infection, EBV remains dormant in host cells for long periods of time. However, the presence or episodic reactivation of the virus increases the risk of transforming healthy cells to malignant cells that routinely escape host immune surveillance or of producing pathogenic autoantibodies. Cancers caused by EBV display distinct molecular behaviors compared to those of the same tissue type that are not caused by EBV, presenting opportunities for targeted treatments. Despite some encouraging results from exploration of vaccines, antiviral agents and immune- and cell-based treatments, the efficacy and safety of most therapeutics remain unclear. Here, we provide an up-to-date review focusing on underlying immune and environmental mechanisms, current therapeutics and vaccines, animal models and emerging technologies to study EBV-associated diseases that may help provide insights for the development of novel effective treatments.
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Affiliation(s)
- Srishti Chakravorty
- Department of Biochemistry, Purdue University, West Lafayette, IN, United States
| | - Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Majid Kazemian
- Department of Biochemistry, Purdue University, West Lafayette, IN, United States.,Department of Computer Science, Purdue University, West Lafayette IN, United States
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18
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Vitiello GAF, Ferreira WAS, Cordeiro de Lima VC, Medina TDS. Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment. Front Immunol 2021; 12:782852. [PMID: 34925363 PMCID: PMC8674309 DOI: 10.3389/fimmu.2021.782852] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/15/2021] [Indexed: 12/22/2022] Open
Abstract
In recent years, it became apparent that cancers either associated with viral infections or aberrantly expressing endogenous retroviral elements (EREs) are more immunogenic, exhibiting an intense intra-tumor immune cell infiltration characterized by a robust cytolytic apparatus. On the other hand, epigenetic regulation of EREs is crucial to maintain steady-state conditions and cell homeostasis. In line with this, epigenetic disruptions within steady-state cells can lead to cancer development and trigger the release of EREs into the cytoplasmic compartment. As such, detection of viral molecules by intracellular innate immune sensors leads to the production of type I and type III interferons that act to induce an antiviral state, thus restraining viral replication. This knowledge has recently gained momentum due to the possibility of triggering intratumoral activation of interferon responses, which could be used as an adjuvant to elicit strong anti-tumor immune responses that ultimately lead to a cascade of cytokine production. Accordingly, several therapeutic approaches are currently being tested using this rationale to improve responses to cancer immunotherapies. In this review, we discuss the immune mechanisms operating in viral infections, show evidence that exogenous viruses and endogenous retroviruses in cancer may enhance tumor immunogenicity, dissect the epigenetic control of EREs, and point to interferon pathway activation in the tumor milieu as a promising molecular predictive marker and immunotherapy target. Finally, we briefly discuss current strategies to modulate these responses within tumor tissues, including the clinical use of innate immune receptor agonists and DNA demethylating agents.
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Affiliation(s)
| | - Wallax Augusto Silva Ferreira
- Translational Immuno-Oncology Group, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil
- Laboratory of Cytogenomics and Environmental Mutagenesis, Environment Section (SAMAM), Evandro Chagas Institute, Ananindeua, Brazil
| | | | - Tiago da Silva Medina
- Translational Immuno-Oncology Group, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil
- National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo, Brazil
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19
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Díaz Del Arco C, Ortega Medina L, Estrada Muñoz L, García Gómez de Las Heras S, Fernández Aceñero MJ. Is there still a place for conventional histopathology in the age of molecular medicine? Laurén classification, inflammatory infiltration and other current topics in gastric cancer diagnosis and prognosis. Histol Histopathol 2021; 36:587-613. [PMID: 33565601 DOI: 10.14670/hh-18-309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer-related deaths worldwide. In western countries, more than half of GC patients are diagnosed at advanced stages and 5-year survival rates range between 20-30%. The only curative treatment is surgery, and despite recent advances in oncological therapies, GC prognosis is still poor. The main prognostic tool for patient categorization and treatment selection is the TNM classification, but its limitations are being increasingly recognized. Early recurrences may occur in early-stage disease, and patients at the same stage show heterogeneous outcomes. Thus, there is a need to improve GC stratification and to identify new prognostic factors, which may allow us to select drug-susceptible populations, refine patient grouping for clinical trials and discover new therapeutic targets. Molecular classifications have been developed, but they have not been translated to the clinical practice. On the other hand, histological assessment is cheap and widely available, and it is still a mainstay in the era of molecular medicine. Furthermore, histological features are acquiring new roles as reflectors of the genotype-phenotype correlation, and their potential impact on patient management is currently being analyzed. The aim of this literature review is to provide a modern overview of the histological assessment of GC. In this study, we discuss recent topics on the histological diagnosis of GC, focusing on the current role of Laurén classification and the potential value of new histological features in GC, such as inflammatory infiltration and tumor budding.
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Affiliation(s)
- Cristina Díaz Del Arco
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain.
- Complutense University of Madrid, Madrid, Spain
| | - Luis Ortega Medina
- Complutense University of Madrid, Madrid, Spain
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Mª Jesús Fernández Aceñero
- Complutense University of Madrid, Madrid, Spain
- Department of Surgical Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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20
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Ho WJ, Danilova L, Lim SJ, Verma R, Xavier S, Leatherman JM, Sztein MB, Fertig EJ, Wang H, Jaffee E, Yarchoan M. Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2019-000394. [PMID: 32303615 PMCID: PMC7204805 DOI: 10.1136/jitc-2019-000394] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
Background and aims Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear. Methods We conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)). Results Meta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=−1.4%, 95% CI: −13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC. Conclusion There is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ludmila Danilova
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Su Jin Lim
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Rohan Verma
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Stephanie Xavier
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - James M Leatherman
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Marcelo B Sztein
- Center for Vaccine Development, University of Maryland, Baltimore, Maryland, USA.,Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Elana J Fertig
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.,Institute for Computational Medicine, Mathematical Institute for Data Science, Johns Hopkins University, Baltimore, MD, United States
| | - Hao Wang
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Elizabeth Jaffee
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Pancreatic Cancer Precision Medicine Program, Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA .,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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21
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Mansuri N, Birkman EM, Heuser VD, Lintunen M, Ålgars A, Sundström J, Ristamäki R, Lehtinen L, Carpén O. Association of tumor-infiltrating T lymphocytes with intestinal-type gastric cancer molecular subtypes and outcome. Virchows Arch 2021; 478:707-717. [PMID: 32954467 PMCID: PMC7990841 DOI: 10.1007/s00428-020-02932-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/25/2020] [Accepted: 09/15/2020] [Indexed: 12/28/2022]
Abstract
While host immune response is likely to be important for the prognosis of gastric cancer patients, detailed information on the T lymphocyte infiltration in different gastric cancer subtypes is lacking. Here, we studied the presence of CD3, CD8, and FOXP3 (Forkhead box p3) expressing T lymphocytes in a retrospective cohort of 190 intestinal gastric and gastroesophageal adenocarcinomas. The cancers represented four distinct molecular subtypes: Epstein-Barr virus-positive (EBV+), mismatch-repair-deficient (MMR-D), aberrant TP53, and the "other" subtype. The absolute numbers of CD3+, CD8+, and FOXP3+ T lymphocytes were analyzed in relation with these molecular subtypes and selected clinicopathological parameters. Overall, there was a large variation in the amount of infiltrating T lymphocyte in all molecular subtypes. Among the subtypes, EBV+ cancers differed from the other subtypes in increased lymphocyte infiltration and high CD8+/FOXP3+ ratio. While the TP53 aberrant subtype did not differ in the absolute amount of T lymphocyte, the ratio of CD8+/FOXP3+ and CD3+/FOXP3+ cells was highest in this subtype, possibly reflecting immunosuppression associated with genomic instability. Increased CD3+ and CD8+ T lymphocyte infiltrates were associated with better survival, and remained as independent prognostic factors in a multivariate analysis. This study is the first to investigate lymphocytic infiltration within four molecular subtypes of intestinal-type gastric cancer in a European cohort. The results provide an important addition to the current knowledge of T lymphocyte-dependent immune response in gastric cancer and its prognostic significance.
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Affiliation(s)
- Naziha Mansuri
- Research Center for Cancer, Infections and Immunity, Institute of Biomedicine, University of Turku, Kiinamyllynkatu, 10 20520, Turku, Finland.
| | - Eva-Maria Birkman
- Department of Pathology, University of Turku and Turku University Hospital, Kiinamyllynkatu, 10 20520, Turku, Finland
| | - Vanina D Heuser
- Research Center for Cancer, Infections and Immunity, Institute of Biomedicine, University of Turku, Kiinamyllynkatu, 10 20520, Turku, Finland
| | - Minnamaija Lintunen
- Department of Pathology, University of Turku and Turku University Hospital, Kiinamyllynkatu, 10 20520, Turku, Finland
| | - Annika Ålgars
- Department of Oncology, Turku University Hospital, Kiinamyllynkatu 4-8, 20521, Turku, Finland
| | - Jari Sundström
- Department of Pathology, University of Turku and Turku University Hospital, Kiinamyllynkatu, 10 20520, Turku, Finland
| | - Raija Ristamäki
- Department of Oncology, Turku University Hospital, Kiinamyllynkatu 4-8, 20521, Turku, Finland
| | - Laura Lehtinen
- Research Center for Cancer, Infections and Immunity, Institute of Biomedicine, University of Turku, Kiinamyllynkatu, 10 20520, Turku, Finland
| | - Olli Carpén
- Research Center for Cancer, Infections and Immunity, Institute of Biomedicine, University of Turku, Kiinamyllynkatu, 10 20520, Turku, Finland
- Medicum Research Program in Systems Oncology and HUSLAB, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00014, Helsinki, Finland
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22
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Zhu M, Liang Q, Chen T, Kong Q, Ye G, Yu S, Li X, He Q, Liu H, Hu Y, Yu J, Li G. Identification and validation of methylated differentially expressed miRNAs and immune infiltrate profile in EBV-associated gastric cancer. Clin Epigenetics 2021; 13:22. [PMID: 33514440 PMCID: PMC7845045 DOI: 10.1186/s13148-020-00989-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The recent discovery of cancer/tissue specificity of miRNA has indicated its great potential as a therapeutic target. In Epstein-Barr virus-associated gastric cancer (EBVaGC), host genes are affected by extensive DNA methylation, including miRNAs. However, the role of methylated miRNA in the development of EBVaGC and immune cell infiltration has largely remained elusive. RESULTS After crossmatching the DNA methylation and expression profile of miRNA and mRNA in the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas Research Network (TCGA), we discovered that miR-129-2-3p was significantly suppressed due to hypermethylation on its enhancer in EBVaGC. The differentially expressed genes (DEGs) added up to 30, among which AKAP12 and LARP6 were predicted to be the target genes of miR-129-2-3p and negatively correlated with patients' survival. Accordingly, miR-129-2-3p was significantly down-regulated in tumor samples in 26 (65%) out of 40 cases in our cohort (P < 0.0001). The proliferation, migration and invasion functions of GC cells were significantly promoted when transfected with miR-129-2-3p inhibitor and suppressed when transfected with mimics or treated with 5-aza-2'-deoxycytidine. Moreover, a comprehensive regulation network was established by combining the putative transcription factors, miRNA-mRNA and protein-protein interaction (PPI) analysis. Pathway enrichment analysis showed that cytokine activity, especially CCL20, was the most prominent biological process in EBVaGC development. Immune cell infiltration analysis demonstrated CD4+ T cell, macrophage and dendritic cell infiltrates were significantly enriched for the prognostic-indicated hub genes. CONCLUSION This study has provided a comprehensive analysis of differentially expressed miRNAs and mRNAs associated with genome-wide DNA methylation by integrating multi-source data including transcriptome, methylome and clinical data from GEO and TCGA, QPCR of tumor samples and cell function assays. It also gives a hint on the relationships between methylated miRNA, DEGs and the immune infiltration. Further experimental and clinical investigations are warranted to explore the underlying mechanism and validate our findings.
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Affiliation(s)
- Mansheng Zhu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Qixiang Liang
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Tao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Qian Kong
- Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Gengtai Ye
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Shitong Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Xunjun Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Qinglie He
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yanfeng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
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23
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Sun K, Jia K, Lv H, Wang SQ, Wu Y, Lei H, Chen X. EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives. Front Oncol 2020; 10:583463. [PMID: 33381453 PMCID: PMC7769310 DOI: 10.3389/fonc.2020.583463] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/09/2020] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is the fifth most common malignant tumor and second leading cause of cancer-related deaths worldwide. With the improved understanding of gastric cancer, a subset of gastric cancer patients infected with Epstein–Barr virus (EBV) has been identified. EBV-positive gastric cancer is a type of tumor with unique genomic aberrations, significant clinicopathological features, and a good prognosis. After EBV infects the human body, it first enters an incubation period in which the virus integrates its DNA into the host and expresses the latent protein and then affects DNA methylation through miRNA under the action of the latent protein, which leads to the occurrence of EBV-positive gastric cancer. With recent developments in immunotherapy, better treatment of EBV-positive gastric cancer patients appears achievable. Moreover, studies show that treatment with immunotherapy has a high effective rate in patients with EBV-positive gastric cancer. This review summarizes the research status of EBV-positive gastric cancer in recent years and indicates areas for improvement of clinical practice.
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Affiliation(s)
- Keran Sun
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Keqi Jia
- Department of Pathology, Pathology Department of Hebei Medical University, Shijiazhuang, China
| | - Huifang Lv
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Sai-Qi Wang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yan Wu
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huijun Lei
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaobing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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24
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Exosomes of Epstein-Barr Virus-Associated Gastric Carcinoma Suppress Dendritic Cell Maturation. Microorganisms 2020; 8:microorganisms8111776. [PMID: 33198173 PMCID: PMC7697542 DOI: 10.3390/microorganisms8111776] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022] Open
Abstract
The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells.
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25
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Ghasemi F, Tessier TM, Gameiro SF, Maciver AH, Cecchini MJ, Mymryk JS. High MHC-II expression in Epstein-Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation. Sci Rep 2020; 10:14786. [PMID: 32901107 PMCID: PMC7479113 DOI: 10.1038/s41598-020-71775-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023] Open
Abstract
EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.
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Affiliation(s)
- Farhad Ghasemi
- Department of Surgery, Western University, London, ON, N6A 4V2, Canada
| | - Tanner M Tessier
- Department of Microbiology and Immunology, Western University, London, ON, N6A 3K7, Canada
| | - Steven F Gameiro
- Department of Microbiology and Immunology, Western University, London, ON, N6A 3K7, Canada
| | - Allison H Maciver
- Department of Surgery, Western University, London, ON, N6A 4V2, Canada.,Department of Oncology, Western University, London, ON, N6A 3K7, Canada
| | - Matthew J Cecchini
- Department of Pathology and Laboratory Medicine, Western University and London Health Sciences Centre, London, ON, N6A 5C1, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, Western University, London, ON, N6A 3K7, Canada. .,Department of Oncology, Western University, London, ON, N6A 3K7, Canada. .,Department of Otolaryngology, Head & Neck Surgery, Western University, London, ON, N6A 5W9, Canada. .,London Regional Cancer Program, Lawson Health Research Institute, London, ON, N6C 2R5, Canada. .,London Regional Cancer Program, Room A4-837, 790 Commissioners Rd. East, London, ON, N6A 4L6, Canada.
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26
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The Profile and Role of Tumor-infiltrating Lymphocytes in Hepatocellular Carcinoma: An Immunohistochemical Study. Appl Immunohistochem Mol Morphol 2020; 29:188-200. [PMID: 32769442 DOI: 10.1097/pai.0000000000000865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Accepted: 06/03/2020] [Indexed: 12/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Tumor-infiltrating lymphocytes (TILs) are a class of cells that form the tumor microenvironment and thus have an effect on carcinogenesis. The aim of this study was to investigate the immunohistochemical expression of CD8, CD4, cytotoxic T lymphocyte-associated protein-4 (CTLA-4), and granzyme B in HCC and their correlation with clinicopathologic parameters and prognosis. This study was carried out on 112 cases of HCC. High percentage of CD8+ TILs was associated with large tumors and adjacent noncirrhotic liver. High percentage of CD4+ TILs and high CD4 to CD8 ratio were associated with nonviral etiology, low alpha fetoprotein, and direct acting antiviral treatment. High percentage of CTLA-4-positive TILs tended to be associated with high-grade HCC, while a high percentage of CTLA-4 in tumor cells was associated with multiple lesions and low tumor grade. High percentage of granzyme B+ TILs was associated with low grade, early stage, and absence of tumor recurrence. High CD4 percentage and high CD4/CD8 ratio affected patients' overall survival. There is a dynamic interaction between the different subsets of lymphocytes in the environment of HCC manifested by coparallel expression of CD4 and CD8 augmenting the expression of CTLA-4, and only CD8 augments the expression of granzyme B. This opens the gate for the beneficial role of immunotherapy in the management of HCC, reducing recurrence and improving survival.
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27
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Hui D, Chen J, Jiang Y, Pan Y, Zhang Z, Dong M, Shao C. CD44 +CD24 -/low sphere-forming cells of EBV-associated gastric carcinomas show immunosuppressive effects and induce Tregs partially through production of PGE2. Exp Cell Res 2020; 390:111968. [PMID: 32197932 DOI: 10.1016/j.yexcr.2020.111968] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 03/14/2020] [Accepted: 03/16/2020] [Indexed: 02/06/2023]
Abstract
EBV-associated gastric carcinoma (EBVaGC) is accompanied by massive lymphocyte infiltration, but therapy resistance and tumor progression still occur in patients with EBVaGC. Cancer stem cells (CSCs) are reported to possess immunomodulatory ability that allows them to resist immune-mediated rejection for many tumor types. However, whether and how CSCs in EBVaGC exhibit immunosuppression has not yet been elucidated. We isolated CSC-like sphere-forming cells (SFCs) from EBVaGC cell line SNU-719 using the cancer sphere method. We validated their CSC-associated properties in the expression of the epithelial-mesenchymal transition (EMT)-related genes, the ability to form colonies, and resistance to chemotherapy drug-induced apoptosis and explored their immunomodulatory ability using the coculture system with PBMC (peripheral blood mononuclear cell). These CSC-like SFCs were CD44+CD24-/low and were more tumorigenic than the parental SNU-719 cells in the xenograft mouse model. Remarkably, in the tumor-PBMC co-culturing experiments, these EBVaGC SFCs demonstrated profound immunosuppression by inhibiting the proliferation of PBMCs and T cell activation as well as inducing the generation of regulatory T cells (Tregs). Furthermore, the induction of Tregs was partially dependent on prostaglandin E2 (PGE2) produced from SFCs. Moreover, the presence of high CD44+CD24-/low cells in tumor tissues predicted a decreased disease-free survival in patients with EBVaGC. Our study collectively confirmed the existence and immune resistance of CSCs in EBVaGC and offers new insights into the development of novel anti-EBVaGC strategies by targeting CSCs.
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Affiliation(s)
- Dayang Hui
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China
| | - Jianning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China
| | - Ye Jiang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China
| | - Yuhang Pan
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China
| | - Zhigang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China
| | - Min Dong
- Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China
| | - Chunkui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China.
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28
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Gastric cancer: genome damaged by bugs. Oncogene 2020; 39:3427-3442. [PMID: 32123313 PMCID: PMC7176583 DOI: 10.1038/s41388-020-1241-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/18/2020] [Accepted: 02/20/2020] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. Epstein–Barr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression. In this review, we summarized the related reports about the colonized microorganism in the stomach and discussed their specific roles in gastric tumorigenesis. Meanwhile, we highlighted the therapeutic significance of eradicating the microorganisms in GC treatment.
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29
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Ghasemi F, Gameiro SF, Tessier TM, Maciver AH, Mymryk JS. High Levels of Class I Major Histocompatibility Complex mRNA Are Present in Epstein-Barr Virus-Associated Gastric Adenocarcinomas. Cells 2020; 9:E499. [PMID: 32098275 PMCID: PMC7072773 DOI: 10.3390/cells9020499] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/12/2020] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is responsible for approximately 9% of stomach adenocarcinomas. EBV-encoded microRNAs have been reported as reducing the function of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus, which could allow infected cells to evade adaptive immune responses. Using data from nearly 400 human gastric carcinomas (GCs), we assessed the impact of EBV on MHC-I heavy and light chain mRNA levels, as well as multiple other components essential for antigen processing and presentation. Unexpectedly, mRNA levels of these genes were as high, or higher, in EBV-associated gastric carcinomas (EBVaGCs) compared to normal control tissues or other GC subtypes. This coordinated upregulation could have been a consequence of the higher intratumoral levels of interferon γ in EBVaGCs, which correlated with signatures of increased infiltration by T and natural killer (NK) cells. These results indicate that EBV-encoded products do not effectively reduce mRNA levels of the MHC-I antigen presentation apparatus in human GCs.
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Affiliation(s)
- Farhad Ghasemi
- Department of Surgery, Western University, London, ON N6A 3K7, Canada;
| | - Steven F. Gameiro
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada; (S.F.G.); (T.M.T.)
| | - Tanner M. Tessier
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada; (S.F.G.); (T.M.T.)
| | - Allison H. Maciver
- Department of Surgery and Oncology, Western University, London, ON N6A 3K7, Canada;
| | - Joe S. Mymryk
- Department of Microbiology & Immunology, Oncology and Otolaryngology, Head & Neck Surgery, The Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6C 2R5, Canada
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30
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Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype. Am J Surg Pathol 2020; 43:851-860. [PMID: 30969179 DOI: 10.1097/pas.0000000000001253] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibition is effective in a subset of patients with advanced gastric cancer. Genomic profiling has revealed the heterogeneity of gastric adenocarcinomas, but the immune microenvironment and predictors of immunotherapy response remain poorly understood. We aimed to better characterize the underlying immune response to gastric cancer. Retrospective review of a prospectively maintained institutional database was performed to identify patients who underwent curative intent resection of gastric adenocarcinoma from 2006 to 2016. Tumors were classified according to modified TCGA subtype: Epstein-Barr virus (EBV)-associated, microsatellite instability (MSI)-high, intestinal as a surrogate for chromosomal instability, diffuse as a surrogate for genomically stable. Tumor-infiltrating leukocytes were measured using immunohistochemistry. Forty-three patients were identified: 6 EBV, 11 MSI, 14 intestinal, 12 diffuse. The most prevalent tumor-infiltrating leukocytes were CD8 T lymphocytes and CD68 macrophages, comprising 15% and 13% of all tumor cells. EBV and MSI tumors were the most infiltrated, harboring 30% to 50% T cells and 20% macrophages. Intestinal tumors contained fewer T cells but disproportionately more macrophages. Diffuse tumors were the least infiltrated. Programmed cell death protein 1 was most frequently expressed in intestinal tumors, whereas 70% of EBV and MSI tumors expressed programmed death-ligand 1. We herein demonstrate a heterogenous immune response to gastric cancer, which varies by tumor subtype and has implications for future immunotherapy trials. Checkpoint inhibition is unlikely to be effective as single-agent therapy against intestinal and diffuse tumors lacking prominent T-cell infiltration or substantial programmed death-ligand 1 expression.
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31
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Jing JJ, Li H, Wang ZY, Zhou H, Sun LP, Yuan Y. Aberrantly methylated-differentially expressed genes and pathways in Epstein-Barr virus-associated gastric cancer. Future Oncol 2020; 16:187-197. [PMID: 31989840 DOI: 10.2217/fon-2019-0649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Aim: To identify the methylated-differentially expressed genes (MDEGs) that may serve as diagnostic markers and therapeutic targets in Epstein-Barr virus-associated gastric cancer (EBVaGC) and to explore the methylation-based pathways for elucidating biological mechanisms of EBVaGC. Materials & methods: Gene expression and methylation profiles were downloaded from GEO database. MDEGs were identified by GEO2R. Pathway enrichment analyses were conducted based on DAVID database. Hub genes were identified by Cytoscape, which were further verified by The Cancer Genome Atlas database. Results: A total of 367 hypermethylated, lowly expressed genes were enriched in specific patterns of cell differentiation. 31 hypomethylated, highly expressed genes demonstrated enrichment in regulation of immune system process. After validation using The Cancer Genome Atlas database, seven genes were confirmed to be significantly different hub genes in EBVaGC. Conclusion: EBVaGC-specific MDEGs and pathways can be served as potential biomarkers for precise diagnosis and treatment of EBVaGC and provide novel insights into the mechanisms involved.
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Affiliation(s)
- Jing-Jing Jing
- Tumor Etiology & Screening Department of Cancer Institute & General Surgery, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of Cancer Etiology & Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of GI Cancer Etiology & Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, PR China
| | - Hao Li
- Tumor Etiology & Screening Department of Cancer Institute & General Surgery, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of Cancer Etiology & Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of GI Cancer Etiology & Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, PR China
| | - Ze-Yang Wang
- Tumor Etiology & Screening Department of Cancer Institute & General Surgery, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of Cancer Etiology & Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of GI Cancer Etiology & Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, PR China
| | - Heng Zhou
- Department of Anesthesiology, the First Hospital of China Medical University, Shenyang 110001, PR China
| | - Li-Ping Sun
- Tumor Etiology & Screening Department of Cancer Institute & General Surgery, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of Cancer Etiology & Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of GI Cancer Etiology & Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, PR China
| | - Yuan Yuan
- Tumor Etiology & Screening Department of Cancer Institute & General Surgery, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of Cancer Etiology & Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang 110001, PR China.,Key Laboratory of GI Cancer Etiology & Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, PR China
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Moore A, Hikri E, Goshen-Lago T, Barkan T, Morgenstern S, Brook E, Maderer A, Roth W, Gordon N, Kashtan H, Brenner B, Moehler M, Aharon IB. Young-onset gastric cancer and Epstein-Barr Virus (EBV) - a major player in the pathogenesis? BMC Cancer 2020; 20:34. [PMID: 31937281 PMCID: PMC6961297 DOI: 10.1186/s12885-020-6517-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 01/06/2020] [Indexed: 12/30/2022] Open
Abstract
Objective Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC. Methods Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. Results Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002). Conclusion Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.
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Affiliation(s)
- Assaf Moore
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel. .,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel.
| | - Elad Hikri
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| | - Tal Goshen-Lago
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Tamar Barkan
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| | - Sara Morgenstern
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel.,Department of Pathology, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Elena Brook
- Department of Pathology, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Annett Maderer
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Wilfried Roth
- Tissue Bank and Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Noa Gordon
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Hanoch Kashtan
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel.,Department of surgery B, Beilinson campus, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Baruch Brenner
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| | - Markus Moehler
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Irit Ben Aharon
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
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33
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Thirty years of Epstein-Barr virus-associated gastric carcinoma. Virchows Arch 2019; 476:353-365. [PMID: 31836926 DOI: 10.1007/s00428-019-02724-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/18/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the 'gastritis-infection-cancer sequence', followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.
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Gasenko E, Isajevs S, Camargo MC, Offerhaus GJA, Polaka I, Gulley ML, Skapars R, Sivins A, Kojalo I, Kirsners A, Santare D, Pavlova J, Sjomina O, Liepina E, Tzivian L, Rabkin CS, Leja M. Clinicopathological characteristics of Epstein-Barr virus-positive gastric cancer in Latvia. Eur J Gastroenterol Hepatol 2019; 31:1328-1333. [PMID: 31569122 PMCID: PMC8560222 DOI: 10.1097/meg.0000000000001521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Epstein-Barr virus (EBV)-associated gastric cancer has been proposed to be a distinct gastric cancer molecular subtype. The prognostic significance of EBV infection in gastric cancer remains unclear and needs further investigation. Our study aimed to analyze EBV-positive and EBV-negative gastric cancer patients regarding their personal and tumor-related characteristics, and compare their overall survival. METHODS Gastric cancer patients consecutively treated at the Riga East University Hospital during 2009-2016 were identified retrospectively. Tumor EBV status was determined by in-situ hybridization for EBV-encoded RNA (EBER). Information about clinicopathological characteristics was obtained from patient questionnaires, hospital records. Overall survival was ascertained through 30 July 2017. Cox proportional hazard regression models adjusted for personal and tumor-related covariates compared survival between EBV-positive and EBV-negative patients. RESULTS There were a total of 302 gastric cancer patients (61% males) with mean and SD age 63.6 ± 11.5 years. EBER positivity was present in 8.6% of tumors. EBV-positive gastric cancer patients had better survival at 80 months [adjusted hazard ratio = 0.37, 95% confidence interval (CI) = 0.19-0.72] compared to EBV-negative patients. Worse survival was observed for patients with stage III (hazard ratio = 2.76, 95% CI = 1.67-4.56) and stage IV (hazard ratio = 10.02, 95% CI = 5.72-17.57) compared to stage I gastric cancer, and overlapping and unspecified subsite (hazard ratio = 1.85; 95% CI = 1.14; 3.00) compared to distal tumors. CONCLUSION Tumor EBV positivity is a favorable prognostic factor in gastric cancer.
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Affiliation(s)
- Evita Gasenko
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Sergejs Isajevs
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
- Academic Histology Laboratory, Riga, Latvia
| | - M. Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Inese Polaka
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Institute of Information Technology, Riga Technical University, Riga, Latvia
| | - Margaret L. Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Roberts Skapars
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Armands Sivins
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Ilona Kojalo
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Arnis Kirsners
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
- Institute of Information Technology, Riga Technical University, Riga, Latvia
| | - Daiga Santare
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
| | - Jelizaveta Pavlova
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
| | - Olga Sjomina
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
| | - Elina Liepina
- Riga East University Hospital, Riga, Latvia
- The Centre of Disease Prevention and Control of Latvia, Riga, Latvia
| | - Liliana Tzivian
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Charles S. Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Marcis Leja
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga, Latvia
- Faculty of Medicine, University of Latvia, Riga, Latvia
- Riga East University Hospital, Riga, Latvia
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Danilova NV, Malkov PG, Oleynikova NA, Mikhailov IA. [Epstein-Barr virus-associated gastric adenocarcinoma]. Arkh Patol 2019; 81:74-83. [PMID: 31317934 DOI: 10.17116/patol20198103174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
EBV-associated gastric adenocarcinoma accounts for 10% of all gastric adenocarcinomas. The main known facts about the pathogenesis of EBV-associated gastric adenocarcinoma are presented. There are two main morphological types: gastric carcinoma with lymphoid stroma - GCLS (including lymphoepithelioma-like carcinoma; carcinoma with Crohn's disease-like lymphoid reaction; EBV-associated carcinoma with osteoclast-like giant cells) and conventional type adenocarcinoma. EBV-associated gastric adenocarcinomas predominantly express markers of gastric differentiation (MUC5AC, MUC6, CLDN-18) and a number of viral markers (EBER-1, EBNA-1 and BART mRNA). Three types of EBV latent cycle depending on the set of expressed viral transcripts are distinguished. It is believed that EBV-associated gastric adenocarcinoma is characterized by an intermediate position between latent cycles of types 1 and 2. The main method of virus identification is in situ hybridization with the detection of Epstein-Barr virus-encoded small RNAs (EBER-ISH).
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Affiliation(s)
- N V Danilova
- Federal State Educational Institution of Higher Professional Education M.V. Lomonosov Moscow State University, Moscow, Russia
| | - P G Malkov
- Federal State Educational Institution of Higher Professional Education M.V. Lomonosov Moscow State University, Moscow, Russia; Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia, Moscow, Russia
| | - N A Oleynikova
- Federal State Educational Institution of Higher Professional Education M.V. Lomonosov Moscow State University, Moscow, Russia
| | - I A Mikhailov
- Federal State Educational Institution of Higher Professional Education M.V. Lomonosov Moscow State University, Moscow, Russia
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Zubarayev M, Min EK, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol 2019; 4:59. [PMID: 31559340 DOI: 10.21037/tgh.2019.08.05] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022] Open
Abstract
For accurately predicting prognosis and for effectively describing cancer states at a certain point during treatment to other care providers and patients, various staging systems have been utilized in gastric cancer. Among these, the UICC/AJCC tumor-node-metastasis (TNM) staging system is most widely used. However, even within the same substage, gastric cancers can vary substantially in regards to prognosis after treatment. For more accurate and individualized prognostication, staging systems have been found to benefit from including molecular markers and genomic subtypes, in addition to clinicopathological parameters, such as age, sex, tumor size, tumor location, Lauren classification, number of lymph nodes resected, extent of surgical resection, lymphovascular invasion, and adjuvant chemotherapy. In this review article, we review and summarize relevant biomarkers for gastric cancer that can be incorporated into the current anatomy-based TNM staging system, as well as results from validation studies thereof.
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Affiliation(s)
- Mykola Zubarayev
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,GI laparoscopic & Robotic Surgery, National Cancer Institute, Kiev, Ukraine
| | - Eun-Ki Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Taeil Son
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,Gastric Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea
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37
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Qiu MZ, He CY, Lu SX, Guan WL, Wang F, Wang XJ, Jin Y, Wang FH, Li YH, Shao JY, Zhou ZW, Yun JP, Xu RH. Prospective observation: Clinical utility of plasma Epstein-Barr virus DNA load in EBV-associated gastric carcinoma patients. Int J Cancer 2019; 146:272-280. [PMID: 31162842 DOI: 10.1002/ijc.32490] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 05/21/2019] [Accepted: 05/23/2019] [Indexed: 12/13/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.
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Affiliation(s)
- Miao-Zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Cai-Yun He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shi-Xun Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao-Jian Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Medical Oncology, Ganzhou Cancer Hospital, Ganzhou, China
| | - Ying Jin
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jian-Yong Shao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi-Wei Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing-Ping Yun
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Abstract
PURPOSE OF REVIEW Novel immunotherapies such as checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells are leading to promising responses when treating solid tumors and hematological malignancies. T cell neoplasms include leukemia and lymphomas that are derived from T cells and overall are characterized by poor clinical outcomes. This review describes the rational and preliminary results of immunotherapy for patients with T cell lymphoma and leukemia. RECENT FINDINGS For T cell neoplasms, despite significant research effort, only few agents, such as monoclonal antibodies and allogeneic stem cell transplantation, showed some clinical activity. One of the major hurdles to targeting T cell neoplasms is that activation or elimination of T cells, either normal or neoplastic, can cause significant toxicity. A need to develop novel safe and effective immunotherapies for T cell neoplasms exists. In this review, we will discuss the rationale for immunotherapy of T cell leukemia and lymphoma and present the most recent therapeutic approaches.
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Expression of CCL21 by EBV-associated gastric carcinoma cells protects CD8 +CCR7 + T lymphocytes from apoptosis via the mitochondria-mediated pathway. Pathology 2018; 50:613-621. [PMID: 30149990 DOI: 10.1016/j.pathol.2018.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 04/25/2018] [Accepted: 05/17/2018] [Indexed: 11/24/2022]
Abstract
About 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV), which are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are usually accompanied by massive lymphocytes infiltration, among which CD8+ T cells are predominant. To date, the apoptosis of the infiltrating CD8+ T cells in EBVaGC has not been investigated. In the present study, we assessed the immunophenotype and apoptosis of tumour infiltrating lymphocytes (TILs) in both EBVaGC and EBV-negative gastric carcinoma (EBVnGC). We found that CD8+CCR7+ T lymphocytes were increased in EBVaGC compared to EBVnGC [60.53 ± 28.41/high power fields (HPF) vs 19.63 ± 15.97/HPF; p < 0.001]. Moreover, the apoptosis index of TILs was lower in EBVaGC than that in EBVnGC (1.34 ± 0.90 vs 5.94 ± 3.77; p < 0.001). Given that the CCL21-CCR7 axis is reported to be potentially involved in apoptosis, we examined the expression of CCL21 in both EBVaGC and EBVnGC. We found that CCL21 expression was higher in EBVaGC than in EBVnGC (p < 0.001). We also showed that the expression of CCL21 by EBVaGC cells protected CD8+CCR7+ T lymphocytes from apoptosis. Furthermore, the up-regulation of Bcl-2 contributed to the inhibition of apoptosis in CD8+CCR7+ T cells. Collectively, these findings suggest that expression of CCL21 by EBVaGC cells protects CD8+CCR7+ T lymphocytes from apoptosis via the mitochondria-mediated pathway. To our best knowledge, this is the first study to investigate the apoptosis of CD8+ T cells in EBVaGC.
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40
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The Microenvironment in Epstein-Barr Virus-Associated Malignancies. Pathogens 2018; 7:pathogens7020040. [PMID: 29652813 PMCID: PMC6027429 DOI: 10.3390/pathogens7020040] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/08/2018] [Accepted: 04/11/2018] [Indexed: 12/27/2022] Open
Abstract
The Epstein–Barr virus (EBV) can cause a wide variety of cancers upon infection of different cell types and induces a highly variable composition of the tumor microenvironment (TME). This TME consists of both innate and adaptive immune cells and is not merely an aspecific reaction to the tumor cells. In fact, latent EBV-infected tumor cells utilize several specific mechanisms to form and shape the TME to their own benefit. These mechanisms have been studied largely in the context of EBV+ Hodgkin lymphoma, undifferentiated nasopharyngeal carcinoma, and EBV+ gastric cancer. This review describes the composition, immune escape mechanisms, and tumor cell promoting properties of the TME in these three malignancies. Mechanisms of susceptibility which regularly involve genes related to immune system function are also discussed, as only a small proportion of EBV-infected individuals develops an EBV-associated malignancy.
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Na SJ, Park HL, O JH, Lee SY, Song KY, Kim SH. Correlation Between Infection Status of Epstein-Barr Virus and 18F-Fluorodeoxyglucose Uptake in Patients with Advanced Gastric Cancer. ACTA ACUST UNITED AC 2018; 31:749-753. [PMID: 28652452 DOI: 10.21873/invivo.11126] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/18/2017] [Accepted: 05/27/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Epstein-Barr virus-associated gastric cancer (EBVaGC) is one of the four molecular subtypes of gastric cancer, as defined by the classification recently proposed by The Cancer Genome Atlas. We evaluated the correlation between EBV positivity and 18F-fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography/computed tomography (PET/CT) in patients with gastric cancer. MATERIALS AND METHODS We retrospectively enrolled patients with gastric cancer who underwent pretreatment 18F-FDG PET/CT and subsequent surgical resection, and then were diagnosed with advanced gastric cancer (pathologic stage ≥T2 with any N stage). Maximum standardized uptake values (SUVmax) of gastric cancer were measured by pretreatment 18F-FDG PET/CT. EBV sequences were detected by in situ hybridization (ISH) techniques. We analyzed the correlation between EBV positivity, clinicopathologic features and metabolic activity of the primary tumor. RESULTS A total of 205 patients were included and 15 (7.3%) patients were identified as having EBV-positive gastric cancer. Age, gender, tumor location, and histological type showed no significant differences between EBV-positive and negative groups. EBV-positive cancer is significantly more frequent in the higher-metabolic-tumor group than in the lower one (p=0.032). The mean SUVmax of gastric cancers showed significant differences between EBV-positive and negative groups (9.9±4.2 vs. 7.0±4.8, p=0.026). CONCLUSION The infection status of EBV was significantly related to the 18F-FDG uptake of primary tumors in patients with advanced gastric cancer.
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Affiliation(s)
- Sae Jung Na
- Department of Radiology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hye Lim Park
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Joo Hyun O
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Yong Lee
- Department of Radiology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyo Young Song
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Hoon Kim
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Elevated Levels of Interferon- γ Are Associated with High Levels of Epstein-Barr Virus Reactivation in Patients with the Intestinal Type of Gastric Cancer. J Immunol Res 2017; 2017:7069242. [PMID: 29349089 PMCID: PMC5733903 DOI: 10.1155/2017/7069242] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 09/05/2017] [Accepted: 09/14/2017] [Indexed: 12/13/2022] Open
Abstract
Background The inflammatory response directed against Helicobacter pylori (HP) is believed to be one of the main triggers of the appearance of gastric lesions and their progression to gastric cancer (GC). Epstein-Barr virus (EBV) has been found responsible for about 10% of all GCs, but the inflammatory response has not been studied in GC patients with evidence of high levels of EBV reactivation. Objective To determine the relationship between inflammation and antibodies against EBV reactivation antigens, HP, and the bacterium virulence factor CagA in patients with GC. Methods 127 GC patients, 46 gastritis patients, and 197 healthy subjects were studied. IL-1β, IL-6, IL-8, IL-10, TNF-α, TGF-β, MCP-1, and IFN-γ levels were measured in serum or plasma and compared against the antibody titers of VCA-IgG, HP, and the HP virulence factor CagA. Statistical associations were estimated. Results Significant ORs and positive trends were found between VCA-IgG and IFN-γ, specifically for patients with GC of intestinal type (OR: 6.4, 95% C.I. 1.2–35.4) (p < 0.044). Conclusions We confirmed a positive association between a marker of EBV reactivation and intestinal gastric cancer and present evidence of a correlation with elevated serum levels of IFN-γ, but not with the other cytokines.
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Shimizu S, Miyazaki A, Nakamori K, Nakai H, Ogi K, Hasegawa T, Hiratsuka H. Immunophenotypic analysis of tumor infiltrating lymphocytes in Epstein-Barr virus-negative lymphoepithelial carcinoma of the oral cavity: Report of a case. JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY, MEDICINE, AND PATHOLOGY 2017. [DOI: 10.1016/j.ajoms.2017.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Ma J, Li J, Hao Y, Nie Y, Li Z, Qian M, Liang Q, Yu J, Zeng M, Wu K. Differentiated tumor immune microenvironment of Epstein-Barr virus-associated and negative gastric cancer: implication in prognosis and immunotherapy. Oncotarget 2017; 8:67094-67103. [PMID: 28978018 PMCID: PMC5620158 DOI: 10.18632/oncotarget.17945] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/01/2017] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) has been proposed to be a distinct subtype with a specific immune microenvironment. Here, we evaluated tumor-infiltrating T-cell subsets and the expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in 571 gastric cancers (GCs). Tissue microarrays were stained using EBER in situ hybridization for EBV and using immunohistochemistry for CD4, CD8, Foxp3, PD-1 and PD-L1. GCs were categorized into four types based on CD8+ infiltration and PD-L1 expression. The 5-year overall survival (OS) was evaluated according to EBV infection, T-cell subsets, PD-1 and PD-L1 expression and immune types. Thirty-two (5.3%) EBVaGCs were identified, which were more prevalent for CD8+ (p<0.001) and Foxp3+ (p=0.020) cell infiltration than EBV-negative GCs (EBVnGCs), suggesting a better 5-year OS (p=0.003). CD8+ (p=0.001) and Foxp3+ (p=0.018) cell infiltration was associated with better 5-year OS, whereas PD-L1 expression correlated with a poor 5-year OS (p=0.002). EBVaGC and EBVnGC had heterogeneous immune microenvironment, with CD8+ PD-L1- GC exhibiting the best 5-year OS (p<0.001). GC was an immune ignorant dominant tumor and poor to no T-cell infiltration. An immune type classification algorithm can provide prognostic information and a rational basis for immunotherapy.
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Affiliation(s)
- Jing Ma
- Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China
| | - Jianhui Li
- Department of Infectious Diseases, Tangdu Hospital Affiliated to the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yiming Hao
- Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China
| | - Yongzhan Nie
- Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China
| | - Zengshan Li
- Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China
- The Pathology Department, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Meirui Qian
- Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China
| | - Qiaoyi Liang
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China and The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, Guangdong, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China and The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, Guangdong, China
| | - Musheng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Kaichun Wu
- Fourth Military Medical University, State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, China
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Kang BW, Kim JG, Lee IH, Bae HI, Seo AN. Clinical significance of tumor-infiltrating lymphocytes for gastric cancer in the era of immunology. World J Gastrointest Oncol 2017; 9:293-299. [PMID: 28808502 PMCID: PMC5534397 DOI: 10.4251/wjgo.v9.i7.293] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 02/02/2017] [Accepted: 06/06/2017] [Indexed: 02/05/2023] Open
Abstract
Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth. For gastric cancers, several studies have provided strong evidence that immune cells contribute to determining prognosis. However, the exact role of immune cells in gastric cancer remains unclear. Therefore, this review focuses on the clinical significance of immune cells, especially tumor-infiltrating lymphocytes, in gastric cancer.
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Hwang HK, Kim HI, Kim SH, Choi J, Kang CM, Kim KS, Lee WJ. Prognostic impact of the tumor-infiltrating regulatory T-cell (Foxp3 +)/activated cytotoxic T lymphocyte (granzyme B +) ratio on resected left-sided pancreatic cancer. Oncol Lett 2016; 12:4477-4484. [PMID: 28105157 PMCID: PMC5228542 DOI: 10.3892/ol.2016.5252] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 09/22/2016] [Indexed: 01/10/2023] Open
Abstract
Among the subsets of tumor-infiltrating lymphocytes (TILs), activated cytotoxic T lymphocytes (granzyme B+) have an antitumor effect, while regulatory T lymphocytes [forkhead box P3 (Foxp3)+] suppress the antitumor immune response. The aim of the present study was to investigate the possible associations between TIL subsets and survival outcomes in patients with left-sided pancreatic ductal adenocarcinoma (PDAC). From January 2000 to December 2008, 30 patients who underwent curative distal pancreatectomy without neoadjuvant chemoradiotherapy due to left-sided PDAC were enrolled in the present study. TIL subsets were enumerated by immunohistochemical staining for cluster of differentiation (CD)3, CD4, CD8, Foxp3 and granzyme B in the intra-tumoral areas of tissue blocks. Patients were divided into two groups according to the median value of the absolute counts and relative ratios of TIL subsets. In the univariate analysis, age, gender, tumor size, nodal stage, tumor differentiation and lymphovascular/perineural invasion were not significantly associated with survival outcome. However, low levels of preoperative cancer antigen (CA) 19-9 were associated with a longer overall survival (OS), although the association was not significant (37 vs. 18 months; P=0.061). A high level of granzyme B+ was associated with enhanced disease-free survival (DFS) (25 vs. 10 months; P=0.023), and a low Foxp3+/granzyme B+ ratio was associated with a favorable prognosis in terms of DFS (25 vs. 8 months; P=0.008) and OS (47 vs. 17 months; P=0.003). In the multivariate analysis, the ratio of Foxp3+/granzyme B+ was an independent prognostic factor for determining DFS [Exp(B), 3.060; 95% confidence interval (CI), 1.259-47.436; P=0.014] and OS [Exp(B), 3.580; 95% CI, 1.460-8.780; P=0.005]. Among the clinicopathological factors, low levels of CA 19-9 were significantly associated with a low Foxp3+/granzyme B+ ratio (P=0.016). The results of the present study suggested that a low Foxp3+/granzyme B+ ratio may be useful for predicting a good prognosis in surgically resected left-sided PDAC.
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Affiliation(s)
- Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
| | - Hyoung-Il Kim
- Division of Gastrointestinal Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
| | - Se Hoon Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
| | - Junjeong Choi
- Department of Pharmacy, Yonsei University College of Pharmacy, Incheon 406-840, Republic of Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
| | - Kyung Sik Kim
- Division of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
| | - Woo Jung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea
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Epstein-Barr virus infection serves as an independent predictor of survival in patients with lymphoepithelioma-like gastric carcinoma. Gastric Cancer 2016; 19:852-9. [PMID: 26265391 DOI: 10.1007/s10120-015-0524-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 07/22/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND The pathogenesis and clinicopathologic characteristics of Epstein-Barr virus (EBV)-negative lymphoepithelioma-like gastric carcinoma (LELC) are still unclear. In addition, it remains controversial whether EBV infection itself affects the prognosis of LELC. METHODS Between 1995 and 2011, 145 LELC patients (124 patients with EBV infection and 21 patients without EBV infection) underwent radical gastrectomy with D2 lymph node dissection. The clinicopathologic features and prognosis of EBV-negative LELC cases were compared with those of EBV-positive LELC cases. The median duration of follow-up after surgery was 55 months. Microsatellite instability (MSI) analysis was performed on 20 EBV-negative LELC cases. RESULTS EBV-negative LELC accounted for 14.5 % of the total LELC cases. EBV-negative LELC was significantly associated with older age, female sex, advanced T stage, and advanced American Joint Committee on Cancer (AJCC) tumor stage compared with EBV-positive LELC. In univariate analysis, patients with EBV-negative LELC had significantly shorter overall, disease-specific, and recurrence-free survival than those with EBV-positive LELC. The 5-year overall survival rates were 81.0 % for patients with EBV-negative LELC and 96.2 % for patients with EBV-positive LELC. In a Cox proportional hazards model, EBV infection, age, and AJCC tumor stage were identified as independent predictors of overall survival. MSI-high, MSI-low, and microsatellite-stable tumors accounted for 25, 10, and 65 % of EBV-negative LELC cases, respectively. MSI status did not affect the prognosis of EBV-negative LELC cases. CONCLUSIONS EBV infection serves as an independent predictor of survival in patients with LELC. EBV-negative LELC exhibited clinicopathologic features and prognosis distinct from those of EBV-positive LELC.
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48
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Cho J, Kang MS, Kim KM. Epstein-Barr Virus-Associated Gastric Carcinoma and Specific Features of the Accompanying Immune Response. J Gastric Cancer 2016; 16:1-7. [PMID: 27104020 PMCID: PMC4834615 DOI: 10.5230/jgc.2016.16.1.1] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 03/14/2016] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma (GC), as defined by the novel classification recently proposed by The Cancer Genome Atlas. EBVaGC has several clinicopathological features such as longer survival and higher frequency of lymphoepithelioma-like carcinoma (LELC) and carcinoma with Crohn's disease-like lymphoid reaction that distinguish it from EBV-negative GC. The intensity and pattern of host cellular immune response in GC have been found to significantly correlate with the prognosis of patients with GC, suggesting that immune reaction and tumor microenvironment have critical roles in the progression of GC, and in particular, EBVaGC. Here, we reviewed the cellular and molecular mechanisms underlying prominent immune reactions in patients with EBVaGC. In EBVaGC, deregulation of the expression of immune response-related genes promotes marked intra- or peritumoral immune cell infiltration. The expression of programmed death receptor-ligand 1 is known to be increased in EBVaGC, and therefore, it has been proposed as a favorable prognostic factor for patients with EBVaGC, albeit some data supporting this claim are controversial. Overall, the underlying mechanisms and clinical significance of the host cellular immune response in patients with EBVaGC have not been thoroughly elucidated. Therefore, further research is necessary to better understand the role of tumor microenvironment in EBVaGC.
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Affiliation(s)
- Junhun Cho
- Department of Pathology & Translational Genomics, Samsung Medical Center, Seoul, Korea
| | - Myung-Soo Kang
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Seoul, Korea
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Liu K, Yang K, Wu B, Chen H, Chen X, Chen X, Jiang L, Ye F, He D, Lu Z, Xue L, Zhang W, Li Q, Zhou Z, Mo X, Hu J. Tumor-Infiltrating Immune Cells Are Associated With Prognosis of Gastric Cancer. Medicine (Baltimore) 2015; 94:e1631. [PMID: 26426650 PMCID: PMC4616881 DOI: 10.1097/md.0000000000001631] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 08/20/2015] [Accepted: 08/26/2015] [Indexed: 02/07/2023] Open
Abstract
Immune cells contribute to determining the prognosis of gastric cancer. However, their exact role is less clear. We determined the prognostic significance of different immune cells in intratumoral tissue (T), stromal tissue (S), and adjacent normal tissue (N) of 166 gastric cancer cases and their interactions, including CD3+, CD4+, CD8, CD57+, CD68+, CD66b+, and Foxp3+ cells, and established an effective prognostic nomogram based on the immune reactions. We found high densities of TCD3+, TCD4+, TCD8+, SCD3+, SCD4+, SCD57+, SCD66b+, and NFoxp3+ cells, as well as high TCD8+/SCD8+ ratio, TCD68+/SCD68+ ratio, TCD3+/TFoxp3+ ratio, TCD4+/TFoxp3+ ratio, TCD8+/TFoxp3+ ratio, SCD3+/SFoxp3+ ratio, and SCD4+/SCD8+ ratio were associated with better survival, whereas high densities of TCD66b+, TFoxp3+, SFoxp3+ and NCD66b+ cells as well as high TCD57+/SCD57+ ratio, TCD66b+/SCD66b+ ratio, SCD8+/SFoxp3+ ratio, and TFoxp3+/NFoxp3+ ratio were associated with significantly worse outcome. Multivariate analysis indicated that tumor size, longitudinal tumor location, N stage, TCD68+/SCD68+ ratio, TCD8+/TFoxp3+ ratio, density of TFoxp3+ cells, and TCD66b+/SCD66b+ ratio were independent prognostic factors, which were all selected into the nomogram. The calibration curve for likelihood of survival demonstrated favorable consistency between predictive value of the nomogram and actual observation. The C-index (0.83, 95% CI: 0.78 to 0.87) of our nomogram for predicting prognosis was significantly higher than that of TNM staging system (0.70). Collectively, high TCD68+/SCD68+ ratio and TCD8+/TFoxp3+ ratio were associated with improved overall survival, whereas high density of TFoxp3+ cells and TCD66b+/SCD66b+ ratio demonstrated poor overall survival, which are promising independent predictors for overall survival in gastric cancer.
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Affiliation(s)
- Kai Liu
- From the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, China (KL,KY, BW,HC, XC, XC, LX, WZ, ZZ, JH); Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China (KL,KY, BW,HC, XC, XC, LX, WZ, JH); Department of Pathology, West China Hospital, Sichuan University, China (LJ, DH); Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (FY); Department of Oncology, West China Hospital, Sichuan University, China (QL); and Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China (XM)
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Shinozaki-Ushiku A, Kunita A, Fukayama M. Update on Epstein-Barr virus and gastric cancer (review). Int J Oncol 2015; 46:1421-34. [PMID: 25633561 DOI: 10.3892/ijo.2015.2856] [Citation(s) in RCA: 215] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 12/29/2014] [Indexed: 12/12/2022] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype that accounts for nearly 10% of gastric carcinomas. EBVaGC is defined by monoclonal proliferation of carcinoma cells with latent EBV infection, as demonstrated by EBV-encoded small RNA (EBER) in situ hybridization. EBVaGC has characteristic clinicopathological features, including predominance among males, a proximal location in the stomach, lymphoepithelioma-like histology and a favorable prognosis. EBVaGC belongs to latency type I or II, in which EBERs, EBNA-1, BARTs, LMP-2A and BART miRNAs are expressed. Previous studies have shown that some EBV latent genes have oncogenic properties. Recent advances in genome-wide and comprehensive molecular analyses have demonstrated that both genetic and epigenetic changes contribute to EBVaGC carcinogenesis. Genetic changes that are characteristic of EBVaGC include frequent mutations in PIK3CA and ARID1A and amplification of JAK2 and PD-L1/L2. Global CpG island hypermethylation, which induces epigenetic silencing of tumor suppressor genes, is also a unique feature of EBVaGC and is considered to be crucial for its carcinogenesis. Furthermore, post-transcriptional gene expression regulation by cellular and/or EBV-derived microRNAs has attracted considerable attention. These abnormalities result in significant alterations in gene expression related to cell proliferation, apoptosis, migration and immune signaling pathways. In the present review we highlight the latest findings on EBVaGC from clinicopathological and molecular perspectives to provide a better understanding of EBV involvement in gastric carcinogenesis.
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Affiliation(s)
- Aya Shinozaki-Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Akiko Kunita
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
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