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Yang HC, Fu CF, Qiao LJ, Long GH, Yang LF, Yao B. Relationship between Helicobacter pylori infection and programmed death-ligand 1 in gastric cancer: A meta-analysis. World J Clin Oncol 2025; 16:102397. [DOI: 10.5306/wjco.v16.i4.102397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/04/2024] [Accepted: 02/06/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies worldwide, and Helicobacter pylori (HP) infection is a well-established risk factor for its development. Programmed death-ligand 1 (PD-L1) expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment. While HP infection and PD-L1 expression in GC may be linked, the relationship between them remains unclear, in part because there have been conflicting results reported from various studies.
AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.
METHODS A systematic literature review was conducted using PubMed, Embase, Cochrane Library, and Web of Science databases. Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included. Odds ratios and 95% confidence intervals were calculated to estimate the association. Heterogeneity was assessed using Cochrane’s Q test and I² statistic. A random-effects model was used due to significant heterogeneity across studies.
RESULTS Fourteen studies involving a total of 3069 patients with GC were included. The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues (odd ratio = 1.69, 95% confidence interval: 1.24-2.29, P < 0.001, I2 = 59%). Sensitivity analyses confirmed the robustness of these findings. Subgroup analyses did not show significant variation based on geographic region, sample size, or method of PD-L1 assessment. Publication bias was minimal, as shown by funnel plots and Egger’s regression test.
CONCLUSION HP infection is associated with increased PD-L1 expression in GC, suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
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Affiliation(s)
- Hong-Chang Yang
- Department of Gastroenterology, Longgang Central Hospital of Shenzhen, Shenzhen 518100, Guangdong Province, China
| | - Cheng-Feng Fu
- Department of Oncology, Tongren People’s Hospital, Tongren 554300, Guizhou Province, China
| | - Li-Jun Qiao
- Department of Basic Medical Sciences, Guizhou Health Vocational College, Tongren 554300, Guizhou Province, China
| | - Gen-He Long
- Department of School of Medicine, Guizhou Vocational and Technical College, Tongren 554300, Guizhou Province, China
| | - Li-Fen Yang
- Department of Oncology, Tongren People’s Hospital, Tongren 554300, Guizhou Province, China
| | - Biao Yao
- Department of Oncology, Tongren People’s Hospital, Tongren 554300, Guizhou Province, China
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Chen H, Zheng Q, Jiang Y, Lin L, Yang Y. IDO1 Expression and CD8+ T-Cell Levels Are Useful Prognostic Biomarkers in Preoperative Gastric Cancer Specimens Before Neoadjuvant Chemotherapy. Appl Immunohistochem Mol Morphol 2025; 33:1-9. [PMID: 39636312 DOI: 10.1097/pai.0000000000001238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 06/05/2024] [Indexed: 12/07/2024]
Abstract
The tumor immune microenvironment occupies an important position in gastric cancer. In this study, we investigated the relationship between indoleamine 2,3-dioxygenase 1 (IDO1), programmed cell death 1 ligand (PD-L1) expressioon, and CD8+ T-cell levels and their efficacy and prognostic value in preoperative gastric cancer specimens before neoadjuvant chemotherapy (NAC). A total of 162 patients with locally advanced gastric cancer were collected in this study. IDO1, PD-L1 expression, and CD8+ T-cell levels in the biopsy samples was detected by immunohistochemical staining, and the relationship between these indexes and the patients' clinicopathological parameters, chemotherapeutic efficacy, and prognosis were investigated. The IDO1 positivity rate was 43.2%. High expression of IDO1 was significantly associated with poor chemotherapeutic efficacy, lymph node metastasis (P<0.05). The PD-L1 positivity rate (using the combined positive score) was 38.2%, and was not related to any clinicopathological variable. Higher CD8+ T-cell levels were associated with a lower rate of lymph node metastasis and lower ypTNM stage (P<0.05). Higher CD8+ T-cell levels were negatively correlated with IDO1 expression (r=-0.224, P<0.05) and positively correlated with PD-L1 expression (r=0.254, P<0.05). Cox regression analysis demonstrated that higher CD8+ T-cell levels was an independent risk factor for overall survival (OS) and the expression of IDO1 had a significantly poorer disease-free survival (DFS). Overexpression of IDO1 and lower CD8+ T-cell levels were associated with poor survival in patients with gastric cancer who received neoadjuvant chemotherapy, and overexpression of IDO1 were associated with the poor tumor response. Our data suggest that IDO1 and CD8 testing of biopsy specimens might be a simple and effective prognostic biomarker for gastric cancer, and IDO1 could predict efficacy of neoadjuvant chemotherapy in gastric cancer.
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Affiliation(s)
- Hu Chen
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - QiaoLin Zheng
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Yiting Jiang
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
| | - Yinghong Yang
- Department of Pathology, Fujian Medical University Union Hospital
- Gastrointestinal Cancer Institute, Fujian Medical University, Fuzhou, China
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Kędzierska M, Bańkosz M. Role of Proteins in Oncology: Advances in Cancer Diagnosis, Prognosis, and Targeted Therapy-A Narrative Review. J Clin Med 2024; 13:7131. [PMID: 39685591 DOI: 10.3390/jcm13237131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Modern oncology increasingly relies on the role of proteins as key components in cancer diagnosis, prognosis, and targeted therapy. This review examines advancements in protein biomarkers across several cancer types, including breast cancer, lung cancer, ovarian cancer, and hepatocellular carcinoma. These biomarkers have proven critical for early detection, treatment response monitoring, and tailoring personalized therapeutic strategies. The article highlights the utility of targeted therapies, such as tyrosine kinase inhibitors and monoclonal antibodies, in improving treatment efficacy while minimizing systemic toxicity. Despite these advancements, challenges like tumor resistance, variability in protein expression, and diagnostic heterogeneity persist, complicating universal application. The review underscores future directions, including the integration of artificial intelligence, advanced protein analysis technologies, and the development of combination therapies to overcome these barriers and refine personalized cancer treatment.
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Affiliation(s)
- Magdalena Kędzierska
- Department of Chemotherapy, Medical University of Lodz, Copernicus Memorial Hospital of Lodz, 90-549 Lodz, Poland
| | - Magdalena Bańkosz
- CUT Doctoral School, Faculty of Materials Engineering and Physics, Department of Material Engineering, Cracow University of Technology, 37 Jana Pawla II Av., 31-864 Krakow, Poland
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Zhang LN, Chen JY, Liu YX, Zhang Y, Hong LL, Li XX, Liu SH, Chen SQ, Peng L, Huang YT. Identification of lncRNA dual targeting PD-L1 and PD-L2 as a novel prognostic predictor for gastric cancer. Front Oncol 2024; 14:1341056. [PMID: 39525623 PMCID: PMC11544118 DOI: 10.3389/fonc.2024.1341056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 09/20/2024] [Indexed: 11/16/2024] Open
Abstract
Background Although breakthroughs have been achieved in gastric cancer (GC) therapy with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), the acquisition of high response rate remains a huge challenge for clinicians. It is imperative to identify novel biomarkers for predicting response to immunotherapy and explore alternative therapeutic strategy for GC. Methods The transcriptomic profiles and clinical information of GC patients from The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) database was used to screen differentially expressed lncRNAs between the tumor specimens and the paracancerous tissues. The TargetScan, miRDB and miRcode database were then utilized to construct competing endogenous RNA (ceRNA) networks and identify pivotal lncRNAs. An independent dataset from GEO (GSE70880) and 23 pairs of GC specimens of our cohort were subsequently performed for external validity. The relationship between clinical variables and gene expression were evaluated by Kruskal-wallis test and Wilcoxon signed-rank. The prognostic value of the candidate genes was assessed using Kaplan-Meier analysis and Cox regression models. CIBERSORT and Gene set enrichment analysis (GSEA) were used to determine immune cell infiltration. Gastric adenocarcinoma AGS cells and human embryonic kidney 293T (HEK293T) cells with knockdown of LINC01094 were generated by siRNA transfection, followed by detecting the alteration of the target miRNA and PD-L1/PD-L2 by RT-qPCR. Besides, the interaction between lncRNA and the miRNA-PD-L1/PD-L2 axis were verified by dual luciferase reporter assay. Results Twenty-two intersecting lncRNAs were identified to be PD-L1/PD-L2-related lncRNAs and LINC01094-miR-17-5p-PD-L1/PD-L2 was constructed as a potential ceRNA network. LINC01094 was increased in tumor specimens than adjacent normal samples and was positively associated with advanced tumor stages and EBV and MSI status. Furthermore, LINC01094 expression was an independent risk factor for poor overall survival (OS) in GC patients. CD8+ T cell exhaustion-related genes were enriched in high-LINC01094 tissues and high-PD-L2 group. A strong positive association of LINC01094 expression was established with M2 macrophages, IL-10+ TAM, as well as PD-L1 and PD-L2 levels, therefore a LINC01094-miR-17-5p-IL-10 network was proposed in macrophages. Using the exoRBase database, LINC01094 was assumed in blood exosomes of GC patients The results of knockdown experiments and luciferase reporter assays revealed that LINC01094 interacted with miR-17-5p and served as a miRNA sponge to regulate the expression of PD-L1 and PD-L2. Conclusion LINC01094 dually regulates the expression of PD-L1 and PD-L2 and shapes the immunosuppressive tumor microenvironment via sponging miR-17-5p. LINC01094 may serve as a potential prognostic predictor and therapeutic target in GC.
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Affiliation(s)
- Li-Na Zhang
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiong-Yu Chen
- Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yu-Xin Liu
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yue Zhang
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Liang-Li Hong
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Xin-Xin Li
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Shu-Hui Liu
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Shu-Qin Chen
- Biological Specimen Repository, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Lin Peng
- Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yi-Teng Huang
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
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Chen H, Wei J, Zhu Z, Hou Y. Multifaceted roles of PD-1 in tumorigenesis: From immune checkpoint to tumor cell-intrinsic function. Mol Carcinog 2024; 63:1436-1448. [PMID: 38751009 DOI: 10.1002/mc.23740] [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: 12/21/2023] [Revised: 02/27/2024] [Accepted: 05/04/2024] [Indexed: 07/10/2024]
Abstract
Programmed cell death 1 (PD-1), a key immune checkpoint receptor, has been extensively studied for its role in regulating immune responses in cancer. However, recent research has unveiled a complex and dual role for PD-1 in tumorigenesis. While PD-1 is traditionally associated with immune cells, this article explores its expression in various cancer cells and its impact on cancer progression. PD-1's functions extend beyond immune regulation, as it has been found to both promote and suppress tumor growth, depending on the cancer type. These findings have significant implications for the future of cancer treatment and our understanding of the immune response in the context of cancer. This article calls for further research into the multifaceted roles of PD-1 to optimize its therapeutic potential and improve patient outcomes in the fight against cancer.
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Affiliation(s)
- Huiqing Chen
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Jiayu Wei
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Zhen Zhu
- Zhenjiang Stomatological Hospital, Zhenjiang, China
| | - Yongzhong Hou
- School of Life Sciences, Jiangsu University, Zhenjiang, China
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6
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Plage H, Furlano K, Hofbauer S, Weinberger S, Ralla B, Franz A, Fendler A, de Martino M, Roßner F, Elezkurtaj S, Kluth M, Lennartz M, Blessin NC, Marx AH, Samtleben H, Fisch M, Rink M, Slojewski M, Kaczmarek K, Ecke T, Hallmann S, Koch S, Adamini N, Zecha H, Minner S, Simon R, Sauter G, Weischenfeldt J, Klatte T, Schlomm T, Horst D, Schallenberg S. PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors. BMC Urol 2024; 24:96. [PMID: 38658905 PMCID: PMC11041044 DOI: 10.1186/s12894-024-01482-z] [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: 05/04/2023] [Accepted: 04/11/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. METHODS To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. RESULTS Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2-4) carcinomas (29.3%; p < 0.0001). However, within pT2-4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). CONCLUSION It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma.
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Affiliation(s)
- Henning Plage
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Kira Furlano
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Sebastian Hofbauer
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Sarah Weinberger
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Bernhard Ralla
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Antonia Franz
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Annika Fendler
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Michela de Martino
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Florian Roßner
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Sefer Elezkurtaj
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Henrik Samtleben
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Margit Fisch
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Rink
- Department of Urology, Marienhospital Hamburg, Hamburg, Germany
| | - Marcin Slojewski
- Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland
| | - Krystian Kaczmarek
- Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland
| | - Thorsten Ecke
- Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Steffen Hallmann
- Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Stefan Koch
- Department of Pathology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Nico Adamini
- Department of Urology, Albertinen Hospital, Hamburg, Germany
| | - Henrik Zecha
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Department of Urology, Albertinen Hospital, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Joachim Weischenfeldt
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Biotech Research & Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
- Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
| | - Tobias Klatte
- Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany
| | - Thorsten Schlomm
- Department of Urology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Simon Schallenberg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
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Steiniche T, Georgsen JB, Meldgaard P, Deitz AC, Ayers M, Pietanza MC, Zu K. Molecular epidemiology study of programmed death ligand 1 and ligand 2 protein expression assessed by immunohistochemistry in extensive-stage small-cell lung cancer. Front Oncol 2024; 13:1225820. [PMID: 38269020 PMCID: PMC10807038 DOI: 10.3389/fonc.2023.1225820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 12/04/2023] [Indexed: 01/26/2024] Open
Abstract
Objectives Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well understood. The current study was conducted to address these data gaps. Methods A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS. Results Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios [HRs], 0.35 [95% CI, 0.21-0.61] and 0.50 [95% CI, 0.31-0.82]); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 [95% CI, 0.22-0.75] and 0.44 [95% CI, 0.25-0.79] for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 [95% CI, 0.20-0.64]; adjusted HR, 0.36 [0.18-0.73]). Conclusion PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.
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Affiliation(s)
- Torben Steiniche
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Peter Meldgaard
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Mark Ayers
- Merck & Co., Inc., Rahway, NJ, United States
| | | | - Ke Zu
- Merck & Co., Inc., Rahway, NJ, United States
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8
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Han Z, Wang N, Qiao Q, He X, Wang N. Association of PD-L1 Expression with Clinicopathologic Characters in Gastric Cancer: A Comprehensive Meta-analysis. Curr Med Chem 2024; 31:3198-3216. [PMID: 37921182 DOI: 10.2174/0109298673263784230922060257] [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: 05/24/2023] [Revised: 07/18/2023] [Accepted: 08/16/2023] [Indexed: 11/04/2023]
Abstract
PURPOSE The expression level of programmed death ligand-1(PD-L1) in patients with gastric cancer is the key to determining the use of immune drugs. The relationship between PD-L1 expression level and clinical characteristics is worth exploring. METHODS By setting the search terms correlated to PD-L1 and gastric cancer, a nearly comprehensive search was carried out in four major databases, and the deadline for searching was September 1, 2022. The retrieved documents were further screened by strict inclusion and exclusion criteria after removing the duplication. Next, the quality of the included studies was evaluated with the Newcastle-Ottawa Scale (NOS) scale. Finally, the STATA15.1 software was used to process data and draw plots, and the odds ratios (ORs) were adopted to assess the pooled effect size. RESULTS A total of 85 works of literature were included in this study through screening strictly, and detailed data were extracted after evaluating the quality of the literature. The process of analysis was conducted in the whole population, Asia-Africa population, European and American population, and Asian population with CPS≥1, amd all found that the expression of PD-L1 in gastric cancer was correlated with age, tumor size, EBV infection, Her-2 expression and microsatellite status. However, the subgroup of the region also found some differences in Asian and Western regions, which was interesting and worth studying further. The included research of this study did not have significant publish bias. CONCLUSION After careful analysis, this study found that age (>60 years), tumor size (>5cm), EBV infection (+), Her-2 expression (+), microsatellite status (MSI), and mismatch repair status (dMMR) were risk factors for positive expression of PD-L1 in gastric cancer.
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Affiliation(s)
- Zhuo Han
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Qing Qiao
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
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9
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Zou Y, Wang J, Zhang J, Guo Q, Song Z, Tang H. Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer. Oncol Lett 2024; 27:20. [PMID: 38058467 PMCID: PMC10696633 DOI: 10.3892/ol.2023.14153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 10/11/2023] [Indexed: 12/08/2023] Open
Abstract
The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.
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Affiliation(s)
- Yunlian Zou
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Jinli Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Jinping Zhang
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Qiang Guo
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Zhengji Song
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Hui Tang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
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Avgustinovich AV, Bakina OV, Afanas’ev SG, Spirina LV, Volkov AM. Safety and Efficacy of Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients with a PD-L1 Positive Status: A Case Report. Curr Issues Mol Biol 2023; 45:7642-7649. [PMID: 37754265 PMCID: PMC10529065 DOI: 10.3390/cimb45090481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023] Open
Abstract
INTRODUCTION The landscape of gastric cancer treatment has changed owing to the widespread use of immune checkpoint inhibitors. Autophagy, involved in regulating the immune system, is a potential trigger of immunity in tumors. This study aims to find molecular-based evidence for the effectiveness of FLOT chemotherapy with immune checkpoint inhibitors in gastric cancer patients. MATERIALS AND METHODS Three patients with advanced gastric cancer received FLOT neoadjuvant chemotherapy with immunotherapy and surgery. IHC was used to determine the PD-L1 status. Real-time PCR was used to analyze expression patterns of transcriptional growth factors, AKT/mTOR signaling components, PD-1, PD-L1, PD-L2 and LC3B. The LC3B content was measured via Western blotting analysis. RESULTS The combination of FLOT neoadjuvant chemotherapy and immunotherapy was found to be efficient in patients with a PD-L1-positive status. Gastric tumors with a PD-L1-positive status exhibited autophagy activation and decreased PD-1 expression. CONCLUSIONS FLOT chemotherapy combined with immune checkpoint inhibitors showed high efficacy in gastric cancer patients with a positive PD-L1 status. Autophagy was involved in activating the tumor immunity. Further research is needed to clarify the mechanism of effective anticancer treatment.
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Affiliation(s)
- Alexandra V. Avgustinovich
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, Tomsk 634050, Russia; (A.V.A.); (S.G.A.); (A.M.V.)
| | - Olga V. Bakina
- Institute of Strength Physics and Materials Science of the Siberian Branch of the Russian Academy of Sciences, 2/4 pr. Akademicheskii, Tomsk 634055, Russia;
- Medico-Biological Faculty, Division of Biochemistry and Molcecular Biology with Clinical Laboratory Diagnostics Course, Siberian State Medical University, 2, Moskovsky trakt, Tomsk 634050, Russia
| | - Sergey G. Afanas’ev
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, Tomsk 634050, Russia; (A.V.A.); (S.G.A.); (A.M.V.)
| | - Liudmila V. Spirina
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, Tomsk 634050, Russia; (A.V.A.); (S.G.A.); (A.M.V.)
- Medico-Biological Faculty, Division of Biochemistry and Molcecular Biology with Clinical Laboratory Diagnostics Course, Siberian State Medical University, 2, Moskovsky trakt, Tomsk 634050, Russia
| | - Alexander M. Volkov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5 Kooperativny Street, Tomsk 634050, Russia; (A.V.A.); (S.G.A.); (A.M.V.)
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11
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Ali SM, Helmy DO, Abdelhamid HS, Eldin Abdelmagid Mahmoud MS. Expression of Programmed Death Ligand1 (PD-L1) in Gastric Carcinoma (Histopathological and Immunohistochemical Study). Asian Pac J Cancer Prev 2023; 24:2295-2303. [PMID: 37505759 PMCID: PMC10676478 DOI: 10.31557/apjcp.2023.24.7.2295] [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: 12/21/2022] [Accepted: 06/06/2023] [Indexed: 07/29/2023] Open
Abstract
OBJECTIVES To evaluate immunohistochemical expression of PD-L1 in cases of gastric adenocarcinoma. To correlate PD-L1 immuno-histochemical expression with other available clinico-pathological parameters such as age, sex, grade, stage, lymph node (L.N) metastasis and others. MATERIAL AND METHODS The present retrospective study retrieved the data and archived paraffin blocks of 60 cases of Gastric carcinoma. Immunohistochemical evaluation was done to assess the expressions of PD-L1 in the tumor cells (TC), tumor infiltrated lymphocytes (TILs) and combined positive score (CPS). RESULTS TC PD-L1 expression was detected in 56.7% of cases, TILs PD-L1 expression was detected in 53.3 % of cases and CPS PD-L1 expression was detected in 63.3% of case, with no statistically significant correlation with clinico-pathological parameters except TILs PD-L1 expression showed statistically significant correlation with positive TILs (P value ˂0.019). CONCLUSION Our findings supported the expression of PD-L1 by TC, TILs, and CPS in gastric cancer, with increased expression in a subpopulation of TILs rich in PD-L1 identifying them as potential targets for PD-1/PD-L1 therapy.
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Affiliation(s)
- Safa Mohammed Ali
- Department of Pathology, Faculty of Medicine, Taiz University, Yemen.
| | - Dina Omar Helmy
- Department of Pathology, Faculty of Medicine, Cairo University, Egypt.
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12
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Villarroel-Espindola F, Ejsmentewicz T, Gonzalez-Stegmaier R, Jorquera RA, Salinas E. Intersections between innate immune response and gastric cancer development. World J Gastroenterol 2023; 29:2222-2240. [PMID: 37124883 PMCID: PMC10134417 DOI: 10.3748/wjg.v29.i15.2222] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/07/2022] [Accepted: 03/13/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastric cancer (GC) is the fifth most commonly diagnosed malignancy. It has a reduced prevalence but has maintained its poor prognosis being the fourth leading cause of deaths related to cancer. The highest mortality rates occur in Asian and Latin American countries, where cases are usually diagnosed at advanced stages. Overall, GC is viewed as the consequence of a multifactorial process, involving the virulence of the Helicobacter pylori (H. pylori) strains, as well as some environmental factors, dietary habits, and host intrinsic factors. The tumor microenvironment in GC appears to be chronically inflamed which promotes tumor progression and reduces the therapeutic opportunities. It has been suggested that inflammation assessment needs to be measured qualitatively and quantitatively, considering cell-infiltration types, availability of receptors to detect damage and pathogens, and presence or absence of aggressive H. pylori strains. Gastrointestinal epithelial cells express several Toll-like receptors and determine the first defensive line against pathogens, and have been also described as mediators of tumorigenesis. However, other molecules, such as cytokines related to inflammation and innate immunity, including immune checkpoint molecules, interferon-gamma pathway and NETosis have been associated with an increased risk of GC. Therefore, this review will explore innate immune activation in the context of premalignant lesions of the gastric epithelium and established gastric tumors.
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Affiliation(s)
- Franz Villarroel-Espindola
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Troy Ejsmentewicz
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roxana Gonzalez-Stegmaier
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roddy A Jorquera
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Esteban Salinas
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
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13
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Hirabayashi M, Georges D, Clifford GM, de Martel C. Estimating the Global Burden of Epstein-Barr Virus-Associated Gastric Cancer: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2023; 21:922-930.e21. [PMID: 35963539 DOI: 10.1016/j.cgh.2022.07.042] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Evidence suggests that a fraction of new gastric cancer cases may be etiologically associated with Epstein-Barr virus (EBV), a known carcinogenic agent. We aimed to systematically explore the proportion of EBV-positive gastric cancer. METHODS We did a systematic review (PROSPERO CRD42020164473) from January 1990 to August 2021. For each country and geographical region with available data, pooled prevalence and corresponding 95% confidence intervals (CIs) of EBV in gastric tumors were calculated for 3 subtypes of gastric adenocarcinoma (conventional adenocarcinoma, lymphoepithelioma-like gastric carcinoma, and remnant/stump carcinoma). For conventional adenocarcinoma, prevalence ratios (PRs) were presented for sex, Lauren's classification, gastric cancer stage, and anatomical location of the stomach. RESULTS In 220 eligible studies including over 68,000 cases of conventional gastric adenocarcinoma, EBV prevalence in tumor cells was 7.5% (95% CI, 6.9%-8.1%) and was higher in men compared with women (PR, 2.1; 95% CI, 1.9-2.4), in diffuse type compared with intestinal type (PR, 1.3; 95% CI, 1.1-1.5), and in the proximal region compared with the distal region (PR, 2.5; 95% CI, 2.0-3.1). There was no difference in EBV prevalence by gastric cancer stage. EBV prevalence was 75.9% (95% CI, 62.8%-85.5%) among lymphoepithelioma-like gastric carcinoma and 26.3% (95% CI, 22.2%-32.0%) among remnant or stump carcinoma. CONCLUSIONS Assuming a causal association between EBV and gastric cancer, our findings, when applied to the GLOBOCAN 2020 gastric cancer incidence, suggest that primary prevention such as the development of an effective EBV vaccine might prevent 81,000 EBV-associated gastric cancer cases worldwide annually.
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Affiliation(s)
- Mayo Hirabayashi
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Damien Georges
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Gary M Clifford
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Catherine de Martel
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France.
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14
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Zhu Y, Zhu F, Ba H, Chen J, Bian X. Helicobacter pylori infection and PD-L1 expression in gastric cancer: A meta-analysis. Eur J Clin Invest 2023; 53:e13880. [PMID: 36164962 DOI: 10.1111/eci.13880] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/24/2022] [Accepted: 09/26/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND High expression of programmed death ligand-1 (PD-L1) has been related to good response to immunotherapy patients with gastric cancer (GC). However, the influence of Helicobacter pylori (HP) infection on PD-L1 expression in GC remains unknown. A meta-analysis was performed to evaluate the association between HP infection and PD-L1 expression in GC. METHODS Observational studies that investigated the relationship between HP infection and PD-L1 expression in patients with GC were obtained by search electronic databases, including PubMed, Embase, Cochrane's Library and Web of Science. A random-effect model incorporating the possible influence of between-study heterogeneity was used to pool the results. RESULTS Ten studies with 1870 patients with GC contributed to the meta-analysis. Pooled results showed that HP infection was significantly associated with the tumour expression of PD-L1 (odds ratio [OR]: 1.90, 95% confidence interval: 1.33-2.72, p < .001; I2 = 53%). Subgroup analyses showed that the association between HP infection and PD-L1 expression in GC was not significantly affected by sample size, methods for PD-L1 evaluation and quality score (p for subgroup analyses all >.05). However, a stronger association was observed in studies with higher prevalence of HP infection (≥35%, OR: 2.58) as compared with those with lower prevalence (<35%, OR: 1.45, p for subgroup difference = .04). CONCLUSION Helicobacter pylori infection in GC patients is associated with tumour expression of PD-L1, suggesting HP infection may be a predictor of good response to immunotherapy in GC.
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Affiliation(s)
- Yaodong Zhu
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - Fangyuan Zhu
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - He Ba
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - Jie Chen
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
| | - Xiuliang Bian
- Department of Integrated Traditional and Western Medicine in Oncology, The First Affiliated Hospital of Medical University of Anhui, Hefei, China
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15
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Mokhtari Z, Rezaei M, Sanei MH, Dehghanian A, Faghih Z, Heidari Z, Tavana S. Tim3 and PD-1 as a therapeutic and prognostic targets in colorectal cancer: Relationship with sidedness, clinicopathological parameters, and survival. Front Oncol 2023; 13:1069696. [PMID: 37035199 PMCID: PMC10076872 DOI: 10.3389/fonc.2023.1069696] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 03/08/2023] [Indexed: 04/11/2023] Open
Abstract
Background Colorectal cancer (CRC) is a heterogeneous disease that complicates predicting patients' prognosis and their response to treatment. CRC prognosis is influenced by the tumor microenvironment (TME). The immune system is a critical component of the TME. Programmed cell death receptor 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (Tim3) are inhibitory immune checkpoints that regulate immune response and may provide prognostic power. However, the effect of their expressions and co-expressions on the CRC prognosis remains unclear. Accordingly, this study aimed to investigate the prognostic value of the CD8, CD3, PD-1, Tim3 expression, and PD-1/Tim3 co-expression in patients with CRC. Materials and Methods One hundred and thirty six patients with CRC who underwent curative surgery were enrolled in the study. Immunohistochemical staining was performed for PD-1, Tim3, CD8, and CD3, and the expression of each marker was evaluated in the center of the tumor (CT), invasive margin (IM), and adjacent normal-like tissue. Result Our results indicated that high expression of PD-1 in IM was significantly associated with lower TNM stage, T-stage, M-stage, lack of metastasis, the presence of tertiary lymphoid structure (TLS), lack of recurrence (in the left-sided tumors), and larger tumor size (in right-sided tumors) (P<0.05). High expression of PD-1 in IM was also associated with improved overall survival (OS) in a subgroup of patients with high CD8 expression. High Tim3 expression in CT was associated with higher M-stage (M1) (in left-sided CRCs) (P<0.05). It was also associated with decreased OS in total cohort and left-sided CRCs and represented an independent prognostic factor for CRC patients in multivariate analysis. PD-1 and Tim3 co-expression had no synergistic effects on predicting OS. Conclusion Our findings suggest that the clinicopathological and prognostic significance of immune system-related markers such as CD8, PD-1, and Tim3 depends on the primary tumor sides. We also showed that Tim3 could act as a prognostic factor and therapeutic target in CRC. This marker is probably a more preferred target for immunotherapy than PD-1, especially in left-sided CRCs.
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Affiliation(s)
- Zahra Mokhtari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- *Correspondence: Marzieh Rezaei,
| | - Mohammad Hossein Sanei
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirreza Dehghanian
- Department of Pathology, School of Medicine, Shiraz University of Medical Science, Shiraz, Iran
| | - Zahra Faghih
- Institute for Cancer Research (ICR), School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Heidari
- Department of Biostatistics & Epidemiologyt, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shirin Tavana
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, Kunisaki C, Akazawa Y, Ozawa S, Matsumoto S, Suzuki T, Mitoro A, Fukunaga T, Shimizu A, Fujimoto G, Yao T. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther 2022; 23:191-200. [PMID: 35220884 PMCID: PMC8890430 DOI: 10.1080/15384047.2022.2038002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
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Affiliation(s)
- Tsutomu Yoshida
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Go Ogura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Mikiko Tanabe
- Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takuo Hayashi
- Department of Diagnostic Pathology, Main Hospital, Juntendo University, Tokyo, Japan
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Sohei Matsumoto
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Tokai University, Isehara, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Kashihara, Japan
| | - Tetsu Fukunaga
- Department of Gastroenterology and Minimally Invasive Surgery, School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Lian J, Zhang G, Zhang Y, Liu H, Zhang J, Nan P, Tian W. PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance. Dig Liver Dis 2022; 54:1419-1427. [PMID: 35123909 DOI: 10.1016/j.dld.2022.01.128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 01/10/2022] [Accepted: 01/16/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND The upregulation of programmed death-ligand 1 (PD-L1) and epidermal growth factor receptor 2 (HER2) may play a role in gastric adenocarcinoma (GAC). AIM To study PD-L1 and HER-2 expression and prognosis in GAC. METHODS PD-L1 and HER2 expression was determined in tumor tissues of 75 patients with GAC. The correlations between PD-L1, HER2 expression, and clinicopathological factors were analyzed. RESULTS The positive expression rate for PD-L1 was 57.3% (43/75) and the HER2 over-expression rate was 17.3% (13/75). PD-L1 expression negatively correlated with the grade of GAC differentiation (r =-0.26, P<0.05). Approximately 85% of HER2-positive GACs were found to be PD-L1-positive and PD-L1 expression positively correlated with HER2 overexpression. The TNM stage and combined HER2 and PD-L1 expression were independent prognostic factors affecting the survival of patients with GAC. The median overall survival and recurrence-free survival of groups I (HER2 overexpression and PD-L1 positive), II (HER2 overexpression and PD-L1 negative), III (No HER2 overexpression and PD-L1 positive) and IV (No HER2 overexpression and PD-L1 negative) were (47 (17-77), 15 (0-44), 81 (62-101), and 78 (60-98) months, respectively. CONCLUSION PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression.
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Affiliation(s)
- Jie Lian
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Guanjun Zhang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China.
| | - Yun Zhang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Heng Liu
- Department of Radiology, Affiliated Hospital of Zunyi Medical University, Medical Imaging Center of Guizhou Province, Zunyi, Guizhou 563003, P.R. China
| | - Jiaojiao Zhang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Pengfei Nan
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
| | - Wei Tian
- Department of Pathology, No. 215 Hospital of Shanxi Nuclear Industry, Xianyang 712000, China
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18
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Distinct antibody clones detect PD-1 checkpoint expression and block PD-L1 interactions on live murine melanoma cells. Sci Rep 2022; 12:12491. [PMID: 35864188 PMCID: PMC9304406 DOI: 10.1038/s41598-022-16776-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/15/2022] [Indexed: 12/16/2022] Open
Abstract
Monoclonal antibodies (abs) targeting the programmed cell death 1 (PD-1) immune checkpoint pathway have revolutionized tumor therapy. Because T-cell-directed PD-1 blockade boosts tumor immunity, anti-PD-1 abs have been developed for examining T-cell-PD-1 functions. More recently, PD-1 expression has also been reported directly on cancer cells of various etiology, including in melanoma. Nevertheless, there is a paucity of studies validating anti-PD-1 ab clone utility in specific assay types for characterizing tumor cell-intrinsic PD-1. Here, we demonstrate reactivity of several anti-murine PD-1 ab clones and recombinant PD-L1 with live B16-F10 melanoma cells and YUMM lines using multiple independent methodologies, positive and negative PD-1-specific controls, including PD-1-overexpressing and PD-1 knockout cells. Flow cytometric analyses with two separate anti-PD-1 ab clones, 29F.1A12 and RMP1-30, revealed PD-1 surface protein expression on live murine melanoma cells, which was corroborated by marked enrichment in PD-1 gene (Pdcd1) expression. Immunoblotting, immunoprecipitation, and mass spectrometric sequencing confirmed PD-1 protein expression by B16-F10 cells. Recombinant PD-L1 also recognized melanoma cell-expressed PD-1, the blockade of which by 29F.1A12 fully abrogated PD-1:PD-L1 binding. Together, our data provides multiple lines of evidence establishing PD-1 expression by live murine melanoma cells and validates ab clones and assay systems for tumor cell-directed PD-1 pathway investigations.
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Nakazawa N, Sohda M, Ubukata Y, Kuriyama K, Kimura A, Kogure N, Hosaka H, Naganuma A, Sekiguchi M, Saito K, Ogata K, Sano A, Sakai M, Ogawa H, Shirabe K, Saeki H. Changes in the Gustave Roussy Immune Score as a Powerful Prognostic Marker of the Therapeutic Sensitivity of Nivolumab in Advanced Gastric Cancer: A Multicenter, Retrospective Study. Ann Surg Oncol 2022; 29:7400-7406. [PMID: 35857197 DOI: 10.1245/s10434-022-12226-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/25/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Identification of positive biomarkers for the effects of nivolumab on patients with advanced gastric cancer (AGC) is significant. The Gustave Roussy Immune Score (GRIm-s) is associated with therapeutic resistance of immune checkpoint inhibitors (ICIs) in other cancers. This multicenter, retrospective study was designed to analyze the association of GRIm-s with therapeutic sensitivity of nivolumab in patients with AGC. METHODS We reviewed 58 patients with AGC treated with nivolumab from October 2017 to November 2018 at five participating institutions. We performed blood tests before the start of nivolumab and after administration of two courses. We evaluated the correlation between the best overall response and GRIm-s. Additionally, we focused on the changes in GRIm-s before the start of nivolumab and after administration of two courses. RESULTS Of the 58 patients, 21 (36.2%) were classified into the disease control (DC) group and 37 (63.8%) into the progressive disease (PD) group. GRIm-s before nivolumab treatment did not correlate with the best therapeutic response (p = 0.086). However, GRIm-s after two courses of nivolumab showed that significantly more PD cases were in the high-risk group (p < 0.0001). After two courses of nivolumab, overall survival was significantly worse in the high-risk group (p < 0.0001). For progression-free survival, the high-risk group had a significantly worse prognosis both before (p = 0.04) and after two courses of nivolumab treatment (p < 0.0001). CONCLUSIONS GRIm-s after two courses of nivolumab and its changes compared to pretreatment values proved beneficial in predicting nivolumab sensitivity.
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Affiliation(s)
- Nobuhiro Nakazawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
| | - Yasunari Ubukata
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Kengo Kuriyama
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Akiharu Kimura
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Norimichi Kogure
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Hisashi Hosaka
- Department of Gastroenterology, Gunma Prefectural Cancer Center, Ota, Gunma, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma, Japan
| | - Masanori Sekiguchi
- Department of Gastroenterology, Isesaki Municipal Hospital, Isesaki, Gunma, Japan
| | - Kana Saito
- Department of Surgery, Japan Community Healthcare Organization Gunma Central Hospital, Maebashi, Gunma, Japan
| | - Kyoichi Ogata
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
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20
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Lima Á, Sousa H, Medeiros R, Nobre A, Machado M. PD-L1 expression in EBV associated gastric cancer: a systematic review and meta-analysis. Discov Oncol 2022; 13:19. [PMID: 35318527 PMCID: PMC8941030 DOI: 10.1007/s12672-022-00479-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated gastric cancer (EBVaGC) and to estimate the expression rate of PD-L1 among this subtype of Gastric Cancer (GC). MATERIALS AND METHODS For this study, PubMed®, EMBASE® and Web of Science® databases were searched for articles published until 1st November 2021. A total of 43 eligible publications with a total of 11,327 patients were included analysis based on inclusion and exclusion criteria. A total of 41 publications present data for proportion estimation and 33 for comparison of PD-L1 between EBV positive and negative GC. DerSimonian-Laird random-effects model was used for meta-analysis. RESULTS The analysis showed that in EBVaGC the pooled positivity rate for PD-L1 was 54.6% (p < 0.001), with a high heterogeneity between the included studies, which was associated with variation on positivity criteria for PD-L1 expression. Overall, the study reveals an increased association between PD-L1 and EBVaGC (OR = 6.36, 95% CI 3.91-10.3, p < 0.001). Furthermore, the study revealed that GC with lymphoid stroma (GCLS) is highly associated with EBV (OR = 17.4, 95% CI 6.83-44.1, p < 0.001), with a pooled EBV positivity rate of 52.9% (p < 0.001). CONCLUSIONS Patients with EBVaGC tend to show higher PD-L1 expression, which enhances EBV positivity as a promising marker for patient selection for immunotherapy targeted agents. A uniform criteria for PD-L1 positivity in tumor cells is needed, as well as further prospective studies to validate our findings and their prognostic significance.
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Affiliation(s)
- Áurea Lima
- Serviço de Oncologia Médica do Centro Hospitalar de Entre o Douro e Vouga, Unidade de Santa Maria da Feira, Rua Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira, Portugal.
- CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal.
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
| | - Hugo Sousa
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Serviço de Virologia, Instituto Português de Oncologia do Porto FG EPE (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Early Phase Clinical Trials Unit - Clinical Research Unit &/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Serviço de Virologia, Instituto Português de Oncologia do Porto FG EPE (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Amanda Nobre
- Serviço de Oncologia Médica do Centro Hospitalar de Entre o Douro e Vouga, Unidade de Santa Maria da Feira, Rua Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira, Portugal
| | - Manuela Machado
- Serviço de Oncologia Médica do Centro Hospitalar de Entre o Douro e Vouga, Unidade de Santa Maria da Feira, Rua Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira, Portugal
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21
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Lee HS, Lee IH, Kang K, Park SI, Jung M, Yang SG, Kwon TW, Lee DY. A Network Pharmacology Perspective Investigation of the Pharmacological Mechanisms of the Herbal Drug FDY003 in Gastric Cancer. Nat Prod Commun 2022; 17. [DOI: 10.1177/1934578x211073030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025] Open
Abstract
Gastric cancer (GC) is one of the most common and deadly malignant tumors worldwide. While the application of herbal drugs for GC treatment is increasing, the multicompound–multitarget pharmacological mechanisms involved are yet to be elucidated. By adopting a network pharmacology strategy, we investigated the properties of the anticancer herbal drug FDY003 against GC. We found that FDY003 reduced the viability of human GC cells and enhanced their chemosensitivity. We also identified 8 active phytochemical compounds in FDY003 that target 70 GC-associated genes and proteins. Gene ontology (GO) enrichment analysis suggested that the targets of FDY003 are involved in various cellular processes, such as cellular proliferation, survival, and death. We further identified various major FDY003 target GC-associated pathways, including PIK3-Akt, MAPK, Ras, HIF-1, ErbB, and p53 pathways. Taken together, the overall analysis presents insight at the systems level into the pharmacological activity of FDY003 against GC.
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Affiliation(s)
- Ho-Sung Lee
- The Fore, Songpa-gu, Seoul, Republic of Korea
- Forest Hospital, Jongno-gu, Seoul, Republic of Korea
| | - In-Hee Lee
- The Fore, Songpa-gu, Seoul, Republic of Korea
| | - Kyungrae Kang
- Forest Hospital, Jongno-gu, Seoul, Republic of Korea
| | - Sang-In Park
- Forestheal Hospital, Songpa-gu, Seoul, Republic of Korea
| | - Minho Jung
- Forest Hospital, Songpa-gu, Seoul, Republic of Korea
| | - Seung Gu Yang
- Kyunghee Naro Hospital, Bundang-gu, Seongnam, Republic of Korea
| | - Tae-Wook Kwon
- Forest Hospital, Jongno-gu, Seoul, Republic of Korea
| | - Dae-Yeon Lee
- The Fore, Songpa-gu, Seoul, Republic of Korea
- Forest Hospital, Jongno-gu, Seoul, Republic of Korea
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22
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Mu L, Wang Y, Su H, Lin Y, Sui W, Yu X, Lv Z. HIF1A-AS2 Promotes the Proliferation and Metastasis of Gastric Cancer Cells Through miR-429/PD-L1 Axis. Dig Dis Sci 2021; 66:4314-4325. [PMID: 33555514 DOI: 10.1007/s10620-020-06819-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastric cancer (GC) is a common leading cause of cancer-related mortality of all malignancies. LncRNA hypoxia-inducible factor-1 alpha antisense RNA-2 (HIF1A-AS2) has been identified to involve in the development of GC. Therefore, we further explored the detailed molecular mechanism of HIF1A-AS2 in GC progression. METHODS The expression of HIF1A-AS2, microRNA-429 (miR-429), and programmed cell death ligand 1 (PD-L1) was measured using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, migration, and invasion abilities were detected by Cell Counting Kit-8 (CCK-8) or transwell assay. The interaction between miR-429 and HIF1A-AS2 or PD-L1 was confirmed by luciferase reporter assay. Murine xenograft model was established to investigate the role of HIF1A-AS2 in vivo. RESULTS HIF1A-AS2 was elevated in GC tissues and cell lines. Functional experiments showed that HIF1A-AS2 knockdown inhibited GC cell proliferation, migration, and invasion in vitro, as well as hindered tumor growth in vivo. Moreover, HIF1A-AS2 directly bound to miR-429 based on bioinformatics prediction and luciferase assay, and inhibition of miR-429 abolished the effects of HIF1A-AS2 knockdown on GC cells. Furthermore, miR-429 directly targeted PD-L1, and overexpression of miR-429 suppressed GC tumorigenesis via PD-L1. Besides that, PD-L1 also performed an oncogenic role in GC cell proliferation and metastasis. Additionally, HIF1A-AS2 could indirectly regulate PD-L1 expression via sponging miR-429. CONCLUSION HIF1A-AS2 is a dependable predictor of malignancy and prognosis in GC and functions as an oncogene to promote GC cell proliferation and metastasis by regulating miR-429/PD-L1 axis, indicating a new insight into the search for novel biomarkers and therapeutic strategies.
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Affiliation(s)
- Linsong Mu
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuding East Rd, Zhifu District, Yantai, 264000, Shangdong, China
| | - Yeli Wang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shangdong, China
| | - Hailong Su
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuding East Rd, Zhifu District, Yantai, 264000, Shangdong, China
| | - Yang Lin
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuding East Rd, Zhifu District, Yantai, 264000, Shangdong, China
| | - Wu Sui
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuding East Rd, Zhifu District, Yantai, 264000, Shangdong, China
| | - Xiang Yu
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuding East Rd, Zhifu District, Yantai, 264000, Shangdong, China
| | - Zhongchuan Lv
- Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20, Yuding East Rd, Zhifu District, Yantai, 264000, Shangdong, China.
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23
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Yang X, Liu J. Targeting PD-L1 (Programmed death-ligand 1) and inhibiting the expression of IGF2BP2 (Insulin-like growth factor 2 mRNA-binding protein 2) affect the proliferation and apoptosis of hypopharyngeal carcinoma cells. Bioengineered 2021; 12:7755-7764. [PMID: 34608837 PMCID: PMC8806995 DOI: 10.1080/21655979.2021.1983278] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Programmed cell death-ligand 1 (PD-L1) have been attracting increasing attention in cancer diagnosis and treatment. The insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is involved in the progression of multiple types of cancer. So, the role of IGF2BP2 and PD-L1 in hypopharyngeal carcinoma was assessed. Western blotting and immunochemistry were used to evaluate the expression of IGF2BP2 and PD-1/PD-L1. IGF2BP2 expression was knocked down in FaDu cells, and the effects on cell viability, apoptosis and proliferation were measured. A tumor-bearing nude model of hypopharyngeal carcinoma was constructed to evaluate the effect of a PD-L1 inhibitor and IGF2BP2 knockdown on hypopharyngeal carcinoma in vivo. RNA pull-down assays were used to assess the interaction between IGF2BP2 and PD-L1. The results showed that knockdown of IGF2BP2 inhibited FaDu cell proliferation and promoted apoptosis, as evidenced by the lower cell viability, a higher ratio of TUNEL-positive cells, decreased expression of Bcl-2 and cyclins, and increased expression of cleaved-caspase 3. In vivo, the tumor volume and weight were reduced by both the PD-L1 inhibitor and IGF2BP2 knockdown. Additionally, the interaction between PD-L1 and IGF2BP2 was confirmed. In conclusion, the results in the present study revealed that inhibition of IGF2BP2 might be a potentially relevant method for treating hypopharyngeal carcinoma, and the effects might be mediated via inhibition of the PD-1/PD-L1 axis.
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Affiliation(s)
- Xudong Yang
- Department of Otolaryngology, First Affiliated Hospital of Soochow University, Soochow, Jiangsu, P.R. China.,Department of Otolaryngology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Jisheng Liu
- Department of Otolaryngology, First Affiliated Hospital of Soochow University, Soochow, Jiangsu, P.R. China
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24
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Abdolahi S, Ghazvinian Z, Muhammadnejad S, Ahmadvand M, Aghdaei HA, Ebrahimi-Barough S, Ai J, Zali MR, Verdi J, Baghaei K. Adaptive NK Cell Therapy Modulated by Anti-PD-1 Antibody in Gastric Cancer Model. Front Pharmacol 2021; 12:733075. [PMID: 34588986 PMCID: PMC8473695 DOI: 10.3389/fphar.2021.733075] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/12/2021] [Indexed: 12/15/2022] Open
Abstract
Recently, adaptive NK cell therapy has become a promising treatment but has limited efficacy as a monotherapy. The identification of immune checkpoint inhibitor (ICI) molecules has opened a new horizon of immunotherapy. Herein, we aimed to demonstrate the cytotoxic effects of a polytherapy consisting of ex vivo expanded IL-2-activated NK cells combined with human anti-PD-1 antibody as an important checkpoint molecule in a xenograft gastric cancer mouse model. EBV-LCL cell is used as a feeder to promote NK cell proliferation with a purity of 93.4%. Mice (NOG, female, 6–8 weeks old) with xenograft gastric tumors were treated with PBS, ex vivo IL-2-activated NK cells, IL-2-activated NK cell along with human anti-PD-1 (Nivolumab), and IL-2-activated pretreated NK cells with anti-PD-1 antibody. The cytotoxicity of ex vivo expanded NK cells against MKN-45 cells was assessed by a lactate dehydrogenase (LDH) assay. Tumor volume was evaluated for morphometric properties, and tumor-infiltrating NK cells were assessed by immunohistochemistry (IHC) and quantified by flow cytometry. Pathologic responses were considered by H and E staining. Ex vivo LDH evaluation showed the cytotoxic potential of treated NK cells against gastric cancer cell line. We indicated that the adoptive transfer of ex vivo IL-2-activated NK cells combined with anti-PD-1 resulted in tumor growth inhibition in a xenograft gastric cancer model. Mitotic count was significantly decreased (*p < 0.05), and the tumor was associated with improved infiltration of NK cells in the NK-anti-PD-1 pretreated group (*p < 0.05). In conclusion, the combination approach of activated NK cells and anti-PD-1 therapy results in tumor growth inhibition, accompanied by tumor immune cell infiltration in the gastric tumor model.
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Affiliation(s)
- Shahrokh Abdolahi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Ghazvinian
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samad Muhammadnejad
- Cell-Based Therapies Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ahmadvand
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Science, Tehran, Iran.,Department of Hematology and Applied Cell Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jafar Ai
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Javad Verdi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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25
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PD-L1 Expression Is a Favorable Prognostic Marker in Gastric Carcinoma. Appl Immunohistochem Mol Morphol 2021; 28:748-754. [PMID: 32205740 DOI: 10.1097/pai.0000000000000834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. Although multidisciplinary therapeutic strategies have improved treatment outcomes, the overall prognosis for patients with GC remains poor. Recently, immunotherapeutic agents targeting immunosuppressive proteins such as anti-programmed death-1 receptor and anti-programmed death ligand-1 (PD-L1) have emerged as effective treatment options for various cancers, including GC. In addition to their therapeutic role, the expression of PD-L1 has been used as a predictive biomarker for programmed death-1/PD-L1 treatment response and has been shown to have a prognostic role in certain cancers. This study aims to evaluate the expression of PD-L1 in GC samples from Jordanian patients and assess its prognostic role as well as its correlation with clinicopathologic variables. Gastrectomy samples from 96 patients diagnosed with gastric adenocarcinoma were included in the study. Immunohistochemistry assay was employed for PD-L1 testing, and the scoring was based on a combined positive score (CPS). It was found that 66.7% of the study samples were positive for PD-L1 (CPS≥1). The expression of PD-L1 was not significantly associated with any of the assessed clinicopathologic variables; however, it was found to be an independent favorable prognostic factor for overall survival (hazard ratio: 0.481; 95% confidence interval: 0.231-1.001; P=0.050).
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26
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Park Y, Seo AN, Koh J, Nam SK, Kwak Y, Ahn SH, Park DJ, Kim HH, Lee HS. Expression of the immune checkpoint receptors PD-1, LAG3, and TIM3 in the immune context of stage II and III gastric cancer by using single and chromogenic multiplex immunohistochemistry. Oncoimmunology 2021; 10:1954761. [PMID: 34367732 PMCID: PMC8312618 DOI: 10.1080/2162402x.2021.1954761] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We sought to determine the clinicopathological significance of PD-1, LAG3, and TIM3 in gastric cancer (GC) by examining their expression and immune context. Immunohistochemistry (IHC) for PD-1, TIM3, LAG3, and tumor-infiltrating immune cell (TIIC) markers was performed in 385 stage II/III GCs. Epstein-Barr virus (EBV) and microsatellite stability (MSI) testing were performed for molecular classification. Chromogenic multiplex IHC (mIHC) for PD1, TIM3, LAG3, CD3, CD8, FOXP3, CD68, and cytokeratin was performed in 58 of the total samples. PD-1, LAG3, and TIM3 expression in TIICs was observed in 91 (23.6%), 193 (50.1%), and 257 (66.8%) GCs by single IHC, respectively. The expression was associated with EBV+ and MSI-H molecular subtypes (p ≤ 0.001). A positive expression of LAG3 in the invasive margin of the tumor was associated with better prognosis in univariate (p = .020) and multivariate (p = .026) survival analyses. The expression of different immune checkpoint receptors (ICRs) was significantly positively correlated. Dual or triple ICR expression was more frequent in high PD-1 and TIM3 density groups than in low-density groups by mIHC (all p ≤ 0.05). ICRs were mainly expressed in CD3+CD8+ and CD3+CD8− T cells. Fifty-eight GCs were classified into three groups by clustering analysis based on mIHC, and the group with the highest ICR expression in TIICs showed significantly better outcomes in progression-free survival (p = .020). In GC, PD-1, LAG3, and TIM3 expression is positively correlated and associated with better prognosis. Our study provides information for the application of effective immune checkpoint inhibitors against GC.
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Affiliation(s)
- Yujun Park
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Soo Kyoung Nam
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yoonjin Kwak
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.,Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea
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Yang B, Ren H, Yu G. Case Report: Squamous Cell Carcinoma of Pancreas With High PD-L1 Expression: A Rare Presentation. Front Oncol 2021; 11:680398. [PMID: 34277425 PMCID: PMC8281219 DOI: 10.3389/fonc.2021.680398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/27/2021] [Indexed: 11/24/2022] Open
Abstract
Primary pancreatic squamous cell carcinoma is sporadic. The diagnosis is usually made following surgery or needle biopsy and requires a thorough workup to exclude metastatic squamous cell carcinoma. Squamous cell carcinoma of the pancreas often has a very poor prognosis. There is no treatment guideline for this type of cancer, and to date, no therapeutic regimen has been proven effective. Here, we report the effectiveness of immunotherapy in combination with chemotherapy against locally advanced squamous cell carcinoma of the pancreas with high programmed cell death ligand 1 (PD-L1) expression. Regional intra-arterial infusion chemotherapy consisting of nab-Paclitaxel followed by gemcitabine infused via gastroduodenal artery every three weeks for two cycles. This therapy resulted in the depletion of carcinoma, and the patient continues to lead a high-quality life with no symptoms for more than 16 months.
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Affiliation(s)
- Baohong Yang
- Oncology Department, Weifang People's Hospital, Weifang Medical University, Weifang, China
| | - Haipeng Ren
- Oncology Department, Weifang People's Hospital, Weifang Medical University, Weifang, China
| | - Guohua Yu
- Oncology Department, Weifang People's Hospital, Weifang Medical University, Weifang, China
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Yang N, Wu Y, Jin M, Jia Z, Wang Y, Cao D, Qin L, Wang X, Zheng M, Cao X, Jiang J. Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer. PeerJ 2021; 9:e11481. [PMID: 34046266 PMCID: PMC8139270 DOI: 10.7717/peerj.11481] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/27/2021] [Indexed: 12/13/2022] Open
Abstract
Background Microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive molecular subtypes exhibit complex immune responses in gastric cancer (GC), and PD-L1 has emerged as a prognostic biomarker associated with the cancer immune microenvironment. This study aimed to determine the prognostic value of molecular subtypes and whether the addition of PD-L1 would accurately predict the prognosis and guide postoperative chemotherapy for GC patients. Methods We performed molecular subtyping of tissue microarray slides from 226 GC patients who were treated with radical gastrectomy. The MSI status and PD-L1 expression were evaluated through immunohistochemistry (IHC) and EBV status through situ hybridization. Multiplex polymerase chain reaction (PCR) was also performed on 50 cases to validate the accuracy of IHC in defining MSI status. Differences in overall survival (OS) were assessed using the Kaplan-Meier method, log-rank test and Cox proportional hazards regression model. Results Among the 226 GC patients, 52 (23.2%) patients were classified as the MSI subtype, 11 (4.9%) were EBV+ subtype, and 161 (71.9%) were MSS (Microsatellite stable) /EBV subtype according to TCGA analysis. Two patients were both positive for MSI and EBV infection. EBV+ cases showed higher PD-L1 positivity than MSI cases and MSS/EBV cases (81.8% vs. 50.0% vs. 35.4%, P = 0.003). Compared with the non-MSS/EBV (MSI or EBV+ cases) subgroup, GC patients with MSS/EBV were associated with the worst outcomes (HR = 1.610, 95% CI [1.0462.479], P = 0.031). MSS/EBV GCs alone could benefit from postoperative chemotherapy (HR = 0.452, 95% CI [0.2990.682], P<0.001), and PD-L1-positive expression could also predict a better prognosis (HR = 0.612, 95% CI [0.3890.962], P = 0.033) in this subgroup. Considering both chemotherapy efficacy and PD-L1 expression in the MSS/EBV subgroup, chemotherapy could improve the prognosis for PD-L1-negative MSS/EBV GCs (HR = 0.357, 95% CI [0.2170.587], P <0.001) but not PD-L1-positive MSS/EBV GCs. Conclusions Molecular subtyping combined with PD-L1 expression could serve as a potential strategy to better predict prognosis and guide postoperative chemotherapy of GC patients.
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Affiliation(s)
- Na Yang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yanhua Wu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Meishan Jin
- Division of Pathology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhifang Jia
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yueqi Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Donghui Cao
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lili Qin
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xueying Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.,Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Min Zheng
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xueyuan Cao
- Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
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Dowell AC, Munford H, Goel A, Gordon NS, James ND, Cheng KK, Zeegers MP, Ward DG, Bryan RT. PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium. Front Oncol 2021; 11:626748. [PMID: 33718196 PMCID: PMC7951139 DOI: 10.3389/fonc.2021.626748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/15/2021] [Indexed: 11/14/2022] Open
Abstract
The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.
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Affiliation(s)
- Alexander C Dowell
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Haydn Munford
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Anshita Goel
- Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Naheema S Gordon
- Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Nicholas D James
- Prostate and Bladder Cancer Research Team, The Institute of Cancer Research, London, United Kingdom
| | - K K Cheng
- School of Health and Population Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Maurice P Zeegers
- Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.,CAPHRI School for Public Health and Primary Care, University of Maastricht, Maastricht, Netherlands
| | - Douglas G Ward
- Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Richard T Bryan
- Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
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PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 2021; 18:345-362. [PMID: 33580222 DOI: 10.1038/s41571-021-00473-5] [Citation(s) in RCA: 815] [Impact Index Per Article: 203.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2021] [Indexed: 02/07/2023]
Abstract
Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1+ disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.
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Qiu Z, Du Y. Clinicopathological and prognostic significance of programmed death ligant-1 expression in gastric cancer: a meta-analysis. J Gastrointest Oncol 2021; 12:112-120. [PMID: 33708429 DOI: 10.21037/jgo-20-568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Gastric cancer (GC) is a common malignant tumor with a high incidence in China. The use of immune checkpoint inhibitors has become the focus of tumor immunotherapy in recent years. This study was to investigate the clinicopathological and prognostic significance of programmed death ligant-1 (PD-L1) expression in GC. Methods We searched the PubMed, ScienceNet, EMbase, CNKI, and Wanfang databases for retrospective cohort studies on the clinicopathology and prognosis of PD-L1 expression in GC published between January 2010 and April 2020. The literature was first selected to extract data according to the inclusion and exclusion criteria, then a meta-analysis performed using Stata15.0 software. Publication bias and sensitivity analysis were carried out for the included studies. Results A total of 3,218 patients in 15 studies were included in the meta-analysis. The positive expression of PD-L1 was related to a decrease in the 3-year survival rate (HR =1.32, 95% CI: 1.02-1.49, P=0.028) and 5-year survival rate (HR =1.39, 95% CI: 1.14-1.69, P=0.001). The difference in PD-L1 expression was related to lymph node metastasis (OR =1.73, 95% CI: 1.18-2.54, P<0.001), but not to tumor stage (OR =1.28, 95% CI: 0.81-2.02, P=0.292). Conclusions The results show that PD-L1 is related to the prognosis of GC. Its high expression decreases the 3- and 5-year survival rates and promotes lymph node metastasis, but does not reflect tumor stage. The results may provide a theoretical basis for the choice of clinical immunotherapy in GC patients.
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Affiliation(s)
- Zhebing Qiu
- Department of Gastrointestinal Tumor Surgery, Shengzhou People's Hospital (the First Affiliated Hospital of Zhejiang University Shengzhou Branch), Shengzhou, China
| | - Yinguo Du
- Department of Gastrointestinal Tumor Surgery, Shengzhou People's Hospital (the First Affiliated Hospital of Zhejiang University Shengzhou Branch), Shengzhou, China
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Prognostic and clinicopathological utility of PD-L2 expression in patients with digestive system cancers: A meta-analysis. Int Immunopharmacol 2020; 88:106946. [PMID: 33182023 DOI: 10.1016/j.intimp.2020.106946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/06/2020] [Accepted: 08/26/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Programmed death ligand-2 (PD-L2)has been detected in various cancers. However, its prognostic value in digestive system cancers (DSCs) remains unclear. Accordingly, this meta-analysis investigated the prognostic and clinicopathological utility of PD-L2 in patients with DSCs. METHODS We systematically searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov., Scopus, and Cochrane Library databases for eligible studies up to April 30, 2020. The hazard ratio (HR), odds ratio (OR), and corresponding 95% confidence interval (CI) of the outcomes were calculated. RESULTS Twenty two studies with 4886 patients were included in this meta-analysis. The pooled results showed that PD-L2 overexpression was significantly associated with poor overall survival (OS) (HR 1.470, 95% CI: 1.252-1.728, p < 0.001) and worse disease-free survival (DFS) (HR1.598, 95% CI: 1.398-1.826, p < 0.001). Subgroup analysis revealed that elevated PD-L2 was a significant prognostic indicator of worse OS in hepatocellular carcinoma (HR 1.703, 95% CI: 1.456-1.991, p < 0.001) and colorectal cancer (HR 3.811, 95% CI: 1.718-8.454, p = 0.001). Concerning clinicopathologic factors, PD-L2 overexpression was associated with lymphatic metastasis (OR 1.394., 95% CI: 1.101-1.764, p = 0.006), tumor metastasis (OR 1.599, 95% CI: 1.072-2.383, p = 0.021), and the histopathological stage (OR 0.704, 95% CI: 0.566-0.875, p = 0.002). CONCLUSION PD-L2 overexpression in DSCs after surgery might predict a poor prognosis, especially in hepatocellular carcinoma and colorectal cancer. Larger patient cohorts are needed to validate its prognostic role.
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Nakayama Y, Mimura K, Kua LF, Okayama H, Min AKT, Saito K, Hanayama H, Watanabe Y, Saito M, Momma T, Saze Z, Ohki S, Suzuki Y, Ichikawa D, Yong WP, Kono K. Immune suppression caused by PD-L2 expression on tumor cells in gastric cancer. Gastric Cancer 2020; 23:961-973. [PMID: 32367440 DOI: 10.1007/s10120-020-01079-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer (GC) patients with PD-L1-negative tumor occasionally have a favorable response to anti-PD-1 mAb. The aim of the present study was to investigate the regulatory mechanism and immunosuppressive role of PD-L2 in GC. METHODS We used immunohistochemistry to evaluate the expression of PD-L2 in primary tumors from 194 patients with GC. The mechanism of PD-L2 expression was assessed in TCGA stomach adenocarcinoma tissue dataset and in vitro assay using GC cell lines. The immunosuppressive role of PD-L2 was evaluated by cytotoxicity of CTL clone against PD-L2 expressing GC cells. RESULTS PD-L2 was expressed on tumor cells (TCs) of 28.4% patients and PD-L2 expression on TCs was significantly associated with tumor progression. TCGA dataset revealed that IFN-γ and, to a lesser extent, IL-4 signature significantly correlated with PD-L2 expression. In vitro assay showed that IFN-γ and, also to a lesser extent, IL-4 can upregulate PD-L2 expression on GC cells. Anti-PD-L2 mAb significantly enhanced the cytotoxicity of CTL clone against GC cell lines expressing PD-L2. CONCLUSIONS PD-L2 is expressed on GC cells and PD-1/PD-L2 interaction are functionally involved in anti-tumor CTL activities. PD-L2 expression should be considered when determining the optimal immunotherapy for GC.
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Affiliation(s)
- Yuko Nakayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan.,First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo-city, Yamanashi, 409-3898, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan. .,Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan. .,Department of Advanced Cancer Immunotherapy, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan. .,Department of Progressive DOHaD Research, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan.
| | - Ley-Fang Kua
- Department of Haematology-Oncology, National University Health System, Singapore, 119228, Singapore
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Aung Kyi Thar Min
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Hiroyuki Hanayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Yohei Watanabe
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Shinji Ohki
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
| | - Yoshiyuki Suzuki
- Department of Radiation Oncology, Fukushima Medical University School of Medicine, Fukushima, Fukushima, 960-1295, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo-city, Yamanashi, 409-3898, Japan
| | - Wei-Peng Yong
- Department of Haematology-Oncology, National University Health System, Singapore, 119228, Singapore.,Cancer Science Institute, National University of Singapore, Singapore, 117599, Singapore
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
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Ubukata Y, Ogata K, Sohda M, Yokobori T, Shimoda Y, Handa T, Nakazawa N, Kimura A, Kogure N, Sano A, Sakai M, Ogawa H, Kuwano H, Shirabe K, Oyama T, Saeki H. Role of PD-L1 Expression during the Progression of Submucosal Gastric Cancer. Oncology 2020; 99:15-22. [PMID: 33113541 DOI: 10.1159/000509033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 05/28/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Programmed death-ligand 1 (PD-L1) expression is a prognostic marker for gastric cancer that correlates with tumor diameter and depth of penetration. But the role of PD-L1 and mechanism(s) employed in the initial phase of invasion in early gastric cancer is yet to be understood. OBJECTIVE This study aims to elucidate the role of PD-L1 during the progression of gastric cancer, specifically invading the submucosa beyond the lamina muscularis mucosa. METHODS Using 107 patients with pathological submucosal gastric cancer, we determined the expression of PD-L1 based on the staining of the cell membrane or cytoplasm of tumor cells in the central and invasive front of the tumor. Samples were categorized into 3 groups based on the intensity of PD-L1 expression. CD8+ lymphocytes expressing PD-1 and CD163+ macrophages were used to determine the number of cell nuclei at the invasive front, similar to PD-L1. CMTM6 levels were determined and used to stratify samples into 3 groups. RESULTS PD-L1 expression was higher in the invasive front (26.2%) than in the central portion of the tumors (7.4%; p < 0.001). Moreover, lymphatic and vascular invasion were more frequently observed in samples with high levels of PD-L1 (lymphatic invasion: 60.7 vs. 35.4%, p = 0.0026, and vascular invasion: 39.3 vs. 16.5%, p = 0.0018). There was no correlation between PD-L1 expression and the levels of PD-1, CD8, CD163, and CMTM6. CONCLUSIONS PD-L1-expressing cancer cells at the invasive front of gastric cancer influence the initial stages of tumor invasion and lymphovascular permeation in early-stage gastric cancers. Immune checkpoint signaling may be the driving force in the invasive front during the invasion of the submucosa beyond the lamina muscularis mucosa.
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Affiliation(s)
- Yasunari Ubukata
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Kyoichi Ogata
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Makoto Sohda
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan,
| | - Takehiko Yokobori
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Yuki Shimoda
- Department of Pathology, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Tadashi Handa
- Department of Pathology, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Nobuhiro Nakazawa
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Akiharu Kimura
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Norimichi Kogure
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Akihiko Sano
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Makoto Sakai
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Hiroomi Ogawa
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Hiroyuki Kuwano
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Ken Shirabe
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Tetsunari Oyama
- Department of Pathology, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
| | - Hiroshi Saeki
- Department of General Surgery, Graduate School of Medical Sciences, Gunma University, Maebashi, Japan
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Solinas C, Aiello M, Rozali E, Lambertini M, Willard-Gallo K, Migliori E. Programmed cell death-ligand 2: A neglected but important target in the immune response to cancer? Transl Oncol 2020; 13:100811. [PMID: 32622310 PMCID: PMC7332529 DOI: 10.1016/j.tranon.2020.100811] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022] Open
Abstract
Programmed cell death-ligand 2 (PD-L2) is one of the two ligands of the programmed cell death-1 (PD-1) receptor, an inhibitory protein mainly expressed on activated immune cells that is targeted in the clinic, with successful and remarkable results. The PD-1/PD-Ls axis was shown to be one of the most relevant immunosuppressive pathways in the immune microenvironment, and blocking this interaction gave rise to an impressive clinical benefit in a broad variety of solid and hematological malignancies. Although PD-L2 has been historically considered a minor ligand, it binds to PD-1 with a two- to six-fold higher affinity as compared to PD-L1. PD-L2 can be expressed by immune, stromal, or tumor cells. The aims of this narrative review are to summarize PD-L2 biology in the physiological responses of the immune system and its role, expression, and clinical significance in cancer.
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Affiliation(s)
- Cinzia Solinas
- Azienda USL Valle d'Aosta, Regional Hospital of Valle d'Aosta, Aosta, Italy
| | - Marco Aiello
- Medical Oncology Unit, A.O.U. Policlinico San Marco, Catania, Italy
| | - Esdy Rozali
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Matteo Lambertini
- IRCCS Ospedale Policlinico San Martino and University of Genova, Genova, Italy
| | | | - Edoardo Migliori
- Columbia University Medical Center, Columbia Center for Translational Immunology, New York, NY, USA.
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Genes Involved in the PD-L1 Pathway Might Associate with Radiosensitivity of Patients with Gastric Cancer. JOURNAL OF ONCOLOGY 2020; 2020:7314195. [PMID: 32963532 PMCID: PMC7495224 DOI: 10.1155/2020/7314195] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/31/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022]
Abstract
The PD-1/PD-L1 pathway plays an important role in the treatment of cancers as immune checkpoint. However, the association of genes involved in the PD-L1 pathway and radiosensitivity of gastric cancer has not been fully characterized. This study aims to explore the relationship between the expression levels of genes involved in the PD-L1 pathway and radiosensitivity for gastric cancer patients. A total of 367 patients with clinical survival information and radiotherapy information were obtained in The Cancer Genome Atlas (TCGA). Genes involved in the PD-L1 pathway were categorized into high and low expression level groups according to the median value. The Cox proportional hazards model was used to find the association between gene expression level and radiosensitivity. The results show that high expression levels of CD274, EGFR, RAF1, RPS6KB1, PIK3CA, MTOR, CHUK, NFKB1, TRAF6, FOS, NFATC1, and HIF1A were associated with radiosensitivity of gastric cancer. While low expression level of HRAS was also associated with radiosensitivity in gastric cancer. The rates of a new tumor event and disease progression were lower for radiosensitivity patients than other patients. The relationship between the expression level of CD274 and other genes involved in the PD-L1 pathway is significant. GO (Gene Ontology) analysis shows that the biological process of 13 genes was mainly related to innate immune response activating the cell surface receptor signaling pathway. KEGG analysis demonstrated that 13 genes in gastric cancer are mainly related to the PD-L1 expression and PD-1 checkpoint pathway in cancer. The correlation between the expression level of CD274 and other genes involved in the PD-L1 pathway is significant. The present study offered more evidence for using PD-L1 and genes involved in the PD-L1 pathway as potential biomarkers to predict radiosensitive patients with gastric cancer.
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Pyo JS, Kim NY, Kang DW. Clinicopathological Significance of EBV-Infected Gastric Carcinomas: A Meta-Analysis. ACTA ACUST UNITED AC 2020; 56:medicina56070345. [PMID: 32668573 PMCID: PMC7404405 DOI: 10.3390/medicina56070345] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/02/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023]
Abstract
Background and objectives: The present study aims to elucidate the clinicopathologic significance of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a meta-analysis. Materials and Methods: Sixty-one eligible studies were included in the present meta-analysis. The included patients, with and without EBV infection, were 2063 and 17,684, respectively. We investigated the clinicopathologic characteristics and various biomarkers, including programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs). Results: The estimated EBV-infected rate of GCs was 0.113 (95% confidence interval (CI): 0.088-0.143). The EBV infection rates in GC cells were 0.138 (95% CI: 0.096-0.194), 0.103 (95% CI: 0.077-0.137), 0.080 (95% CI: 0.061-0.106), and 0.042 (95% CI: 0.016-0.106) in the population of Asia, America, Europe, and Africa, respectively. There was a significant difference between EBV-infected and noninfected GCs in the male: female ratio, but not other clinicopathological characteristics. EBV infection rates were higher in GC with lymphoid stroma (0.573, 95% CI: 0.428-0.706) than other histologic types of GCs. There were significant differences in high AT-rich interactive domain-containing protein 1A (ARID1A) and PD-L1 expressions, and high CD8+ TILs between EBV-infected and noninfected GCs. Conclusions: Our results showed that EBV infection of GCs was frequently found in male patients and GCs with lymphoid stroma. EBV infection was significantly correlated with ARID1A and PD-L1 expressions and CD8+ TILs in GCs.
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Affiliation(s)
- Jung-Soo Pyo
- Department of Pathology, Daejeon Eulji University Hospital, Eulji University School of Medicine, Daejeon 35233, Korea;
| | - Nae-Yu Kim
- Department of Internal Medicine, Daejeon Eulji University Hospital, Eulji University School of Medicine, Daejeon 35233, Korea;
| | - Dong-Wook Kang
- Department of Pathology, Chungnam National University Sejong Hospital, 20 Bodeum 7-ro, Sejong 30099, Korea
- Department of Pathology, Chungnam National University School of Medicine, 266 Munhwa Street, Daejeon 35015, Korea
- Correspondence: ; Tel.: +82-10-8561-9895
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PD-L1 expression increased by IFN-γ via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer. Oncol Lett 2020; 20:1127-1134. [PMID: 32724352 PMCID: PMC7377091 DOI: 10.3892/ol.2020.11647] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 04/03/2020] [Indexed: 01/02/2023] Open
Abstract
PD-L1 inhibitors are widely used in tumor immunotherapy, but their mechanism in colorectal cancer remains unclear. The present study aimed to investigate the mechanisms underlying programmed death ligand 1 (PD-L1) regulation via the interferon-γ (IFN-γ)/janus kinase (JAK)/STAT signaling pathway, and its prognostic value in patients with colorectal cancer (CRC). A cohort of 181 patients were recruited to determine the association between PD-L1 expression and CRC prognosis; the patients were newly diagnosed with colorectal adenocarcinoma and had also undergone a physical tumorectomy. Immunohistochemical staining and survival analysis were used to evaluate the predictive value of PD-L1 protein expression in CRC. Gene set enrichment analysis, RT-qPCR and western blotting, etc were performed to confirm that PD-L1 is regulated by the IFN-γ/JAK/STAT signaling pathway. PD-L1 up-regulation was more frequently observed in patients with larger tumors, positive vascular or lymphatic infiltration and a poorly differentiated stage in addition to being associated with a poor survival in patients with CRC. Following the stimulation with IFN-γ, PD-L1 expression levels were revealed to be increased via the JAK2/STAT1 signaling pathway. In conclusion, the findings of the present study indicated that the expression levels of PD-L1 may be associated with a poor prognosis in patients with CRC. In addition, the results suggested that the IFN-γ-mediated overexpression of PD-L1 in CRC cells may be regulated by the JAK2/STAT1 signaling pathway.
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Ito S, Masuda T, Noda M, Hu Q, Shimizu D, Kuroda Y, Eguchi H, Tobo T, Utsunomiya T, Mimori K. Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer. Oncology 2020; 98:501-511. [PMID: 32380498 DOI: 10.1159/000506075] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 01/22/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. METHODS PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. RESULTS PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC patients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. CONCLUSIONS PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.
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Affiliation(s)
- Shuhei Ito
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Takaaki Masuda
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Miwa Noda
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Qingjiang Hu
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Dai Shimizu
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Yosuke Kuroda
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Hidetoshi Eguchi
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan
| | - Taro Tobo
- Department of Pathology, Kyushu University Beppu Hospital, Beppu, Japan
| | | | - Koshi Mimori
- Department of Surgery and Kyushu University Beppu Hospital, Beppu, Japan,
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Setia N, Ahn S, Han HS, Park DY, Lauwers GY. Predictive value of WHO classification for PD-L1 and Her2/Neu expression and distinct associations with protein expression based classification in gastric carcinoma. Hum Pathol 2019; 94:64-70. [PMID: 31676362 DOI: 10.1016/j.humpath.2019.10.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/13/2019] [Accepted: 10/20/2019] [Indexed: 12/12/2022]
Abstract
The Cancer Genome Atlas data on gastric carcinoma has identified four biologic pathways as potential drivers of gastric carcinogenesis and suggested targeted therapies based on the genomic alterations underscoring each subset. The correlation between morphology, biologic groups and their corresponding biomarkers has been eluded in several previous studies; however, a comprehensive analysis in consideration of the recent advancements has not been performed. In this study we explored the predictive value of morphology for biomarker expression and its association with protein expression based classification of gastric carcinoma. Four hundred eighty six gastric carcinomas which had been classified into protein expression-based groups formed the case cohort. Upon analysis, we found a low positive predictive value of an individual morphologic pattern for biomarker-expression, indicating that an individual morphologic pattern alone cannot predict PD-L1, Her2/neu expression and EBV- or MSI-gastric cancer. A combination approach targeting the test in certain WHO patterns can be employed for maximizing the positive predictive values. These include, PD-L1 testing in tubular, carcinoma with lymphoid stroma, undifferentiated and poorly cohesive patterns and Her2/neu testing in tubular, mixed, papillary, mucinous and solid patterns. The predictive values and morphologic associations presented here have the potential to select patients for personalized therapy.
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Affiliation(s)
- Namrata Setia
- Department of Pathology, University of Chicago, IL, USA 60637.
| | - Sangjeong Ahn
- Department of Pathology, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Republic of Korea 22711.
| | - Hye S Han
- Konkuk University School of Medicine, Seoul, South Korea 501-600.
| | - Do Youn Park
- Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Busan, Republic of Korea 602-739.
| | - Gregory Y Lauwers
- Department of Pathology, H Lee Moffitt Cancer Center and Research Institute, Departments of Oncological Sciences, Pathology and Cell Biology, University of South Florida, Tampa, Florida, USA 33612.
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Gulubova M. Myeloid and Plasmacytoid Dendritic Cells and Cancer - New Insights. Open Access Maced J Med Sci 2019; 7:3324-3340. [PMID: 31949539 PMCID: PMC6953922 DOI: 10.3889/oamjms.2019.735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/06/2023] Open
Abstract
Dendritic cells (DCs) use effective mechanisms to combat antigens and to bring about adaptive immune responses through their ability to stimulate näive T cells. At present, four major cell types are categorised as DCs: Classical or conventional (cDCs), Plasmacytoid (pDCs), Langerhans cells (LCs), and monocyte-derived DCs (Mo-DCs). It was suggested that pDCs, CD1c+ DCs and CD141+ DCs in humans are equivalent to mouse pDCs, CD11b+ DCs and CD8α+ DCs, respectively. Human CD141+ DCs compared to mouse CD8α+ DCs have remarkable functional and transcriptomic similarities. Characteristic markers, transcription factors, toll-like receptors, T helpers (Th) polarisation, cytokines, etc. of DCs are discussed in this review. Major histocompatibility complex (MHC) I and II antigen presentation, cross-presentation and Th polarisation are defined, and the dual role of DCs in the tumour is discussed. Human DCs are the main immune cells that orchestrate the immune response in the tumour microenvironment.
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Affiliation(s)
- Maya Gulubova
- Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
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Wahlin S, Nodin B, Leandersson K, Boman K, Jirström K. Clinical impact of T cells, B cells and the PD-1/PD-L1 pathway in muscle invasive bladder cancer: a comparative study of transurethral resection and cystectomy specimens. Oncoimmunology 2019; 8:e1644108. [PMID: 31646091 PMCID: PMC6791444 DOI: 10.1080/2162402x.2019.1644108] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/10/2019] [Accepted: 07/12/2019] [Indexed: 12/15/2022] Open
Abstract
In patients with muscle invasive bladder cancer (MIBC), neoadjuvant chemotherapy (NAC) prior to radical cystectomy has improved survival but there is an urgent unmet need to identify prognostic and predictive biomarkers to stratify patients who will benefit from treatment. This study aimed to examine the composition of tumor-infiltrating immune cells in MIBC, with particular reference to the clinical outcome and the potential modifying effect of NAC. To this end, the expression of CD8+ and FoxP3+ T cells, CD20+ B cells, PD-1+ and PD-L1+ immune cells and PD-L1+ tumor cells was evaluated by immunohistochemistry on tissue microarrays with paired transurethral resection (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients, 65 of whom had received NAC. Kaplan–Meier and Cox regression analyses were applied to assess the impact of investigated cell subsets on time to recurrence (TTR). In cystectomy specimens, high infiltration of the investigated immune cell populations, but not PD-L1+ tumor cells, were independently associated with a prolonged TTR, whereas in TURB specimens, this association was only seen for CD8+ lymphocytes. An additive beneficial prognostic effect of NAC was seen for the majority of the cell subsets but there was no significant interaction between any immune marker and NAC in relation to TTR. Furthermore, no differences in cell densities prior to NAC treatment were observed between complete and non-complete responders, or pre- and posttreatment in non-complete responders. In conclusion, immune cell infiltration provides important prognostic information in both pre- and postsurgical samples of MIBC, independently of NAC.
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Affiliation(s)
- Sara Wahlin
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund Sweden
| | - Björn Nodin
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund Sweden
| | - Karin Leandersson
- Cancer Immunology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Karolina Boman
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund Sweden
| | - Karin Jirström
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund Sweden
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Valentini AM, Di Pinto F, Coletta S, Guerra V, Armentano R, Caruso ML. Tumor microenvironment immune types in gastric cancer are associated with mismatch repair however, not HER2 status. Oncol Lett 2019; 18:1775-1785. [PMID: 31423245 PMCID: PMC6614673 DOI: 10.3892/ol.2019.10513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 02/18/2019] [Indexed: 12/14/2022] Open
Abstract
The treatment of patients with human epidermal growth factor receptor 2 (HER2)-negative gastric cancer is a major challenge. Immunotherapy using immune checkpoint inhibitors is a rapidly growing field. In a number of malignancy types it has been demonstrated that patients with mismatch repair deficiency efficiently respond to programmed death-ligand 1 (PD-L1) blockade therapy. Recent studies have evaluated tumor microenvironment immune types to predict which patients may clinically benefit from immunotherapy. The present study aimed to evaluate the immunohistochemical expression of PD-L1 in 70 gastric cancer tissue samples. Potential associations between PD-L1 expression and mismatch repair deficiency, HER2 and Epstein Barr virus (EBV) status were then investigated in the context of the tumor microenvironment. A positive association was identified for PD-L1 expression with mismatch repair deficiency and EBV status; however, no association was revealed with HER2 status. Immunohistochemistry was then used to classify the microenvironment immune types. This demonstrated that the majority of the gastric cancer samples (73%) belonged to the tumor microenvironment immune type II [PD-L1-/cluster of differentiation 8 (CD8)+ low], which involves an immune ignorant state and has a low sensitivity to immunotherapy. However, 7% of the gastric cancer cases were identified to belong to the tumor microenvironment immune type I (PD-L1+/CD8+ high), which exhibits adaptive immune escape responses and a high chance of reversion with immune checkpoint blockade therapy. In conclusion, the present study emphasized the importance of evaluating tumor microenvironment immune types, mismatch repair deficiency status and EBV status, rather than PD-L1 expression alone, when evaluating the eligibility of a patient for immunotherapy with anti-programmed cell death protein-1/PD-L1 antibodies.
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Affiliation(s)
- Anna Maria Valentini
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Federica Di Pinto
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Sergio Coletta
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Vito Guerra
- Department of Epidemiology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Raffaele Armentano
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
| | - Maria Lucia Caruso
- Department of Pathology, National Institute of Gastroenterology ‘S. de Bellis’, Research Hospital, Castellana Grotte, I-70013 Bari, Italy
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Wu Y, Zhao T, Jia Z, Cao D, Cao X, Pan Y, Zhao D, Zhang B, Jiang J. Polymorphism of the programmed death-ligand 1 gene is associated with its protein expression and prognosis in gastric cancer. J Gastroenterol Hepatol 2019; 34:1201-1207. [PMID: 30353572 DOI: 10.1111/jgh.14520] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/16/2018] [Accepted: 10/18/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIM While the incidence and mortality of gastric cancer (GC) remains high, and prognosis of GC remains poor, molecules in programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and programmed death-ligand 2 (PD-L2) pathway are promising prognostic biomarker of GC. The polymorphisms on PD-1, PD-L1, and PD-L2 may be associated with their protein expressions and affect the survival of GC patient. METHODS Seven hundred fifty-six GC patients who voluntarily supplied blood samples were enrolled in our study. We genotyped nine polymorphisms on PD-1, PD-L1, and PD-L2, then evaluated the association of the single nucleotide polymorphisms with GC prognosis and analyzed the relationship between the PD-1, PD-L1, and PD-L2 single nucleotide polymorphism genotypes and their protein expression. RESULTS We found that PD-L1 rs822336 CC genotype was independently associated with a better survival of all GC patients and those without postoperative chemotherapy (hazard ratio [HR] = 0.504, 95% confidence interval [CI] = 0.283-0.897 and HR = 0.385, 95% CI = 0.189-0.786). AA+AG genotype of rs2297136 in 3'UTR of the PD-L1 was correlated with the protein expression of PD-L1 protein both in patients overall and those without postoperative chemotherapy (P = 0.013 and P = 0.012). AA+AG genotype of rs2297136 served as an independent factor of better prognosis in patients without postoperative chemotherapy (HR = 0.348, 95% CI = 0.125-0.968). CONCLUSIONS Overall, PD-L1 polymorphisms and protein expression were associated with the prognosis of patients with GC.
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Affiliation(s)
- Yanhua Wu
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
| | - Tiancheng Zhao
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhifang Jia
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
| | - Donghui Cao
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
| | - Xueyuan Cao
- Department of Gastric and Colorectal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yuchen Pan
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
| | - Dan Zhao
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
| | - Bin Zhang
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jing Jiang
- Division of Clinical Research, The First Hospital of Jilin University, Changchun, China
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Knief J, Lazar-Karsten P, Hummel R, Wellner U, Thorns C. PD-L1 expression in carcinoma of the esophagogastric junction is positively correlated with T-cell infiltration and overall survival. Pathol Res Pract 2019; 215:152402. [DOI: 10.1016/j.prp.2019.03.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 02/08/2023]
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Lingohr P, Dohmen J, Semaan A, Branchi V, Dietrich J, Bootz F, Kalff JC, Matthaei H, Dietrich D. Clinicopathological, immune and molecular correlates of PD-L2 methylation in gastric adenocarcinomas. Epigenomics 2019; 11:639-653. [DOI: 10.2217/epi-2018-0149] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Aim: We investigated the significance of PD-L2 DNA methylation in gastric adenocarcinomas. Methods: We analyzed the methylation at different CpG sites within the PD-L2-encoding gene PDCD1LG2 with regard to correlations and associations with gene expression, clinicopathological parameters, molecular features and immune cell infiltrates in two publicly available cohorts (The Cancer Genome Atlas and Singapore cohorts) of a total of 594 gastric adenocarcinoma patients. Results: PD-L2 methylation is significantly associated with transcriptional activity, survival, Epstein–Barr virus infection, PD-L2 gene amplification, CD8+ T-cell infiltration, microsatellite instability and high mutational load (tumor mutational burden, hypermutation). Conclusion: PD-L2 methylation is associated with known predictive biomarkers of response to anti-PD-1 immunotherapies.
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Affiliation(s)
- Philipp Lingohr
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Jonas Dohmen
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | | | | | - Jörn Dietrich
- Department of Otolaryngology, Head & Neck Surgery, University Hospital Bonn, Bonn, Germany
| | - Friedrich Bootz
- Department of Otolaryngology, Head & Neck Surgery, University Hospital Bonn, Bonn, Germany
| | - Jörg C Kalff
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Hanno Matthaei
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Dimo Dietrich
- Department of Otolaryngology, Head & Neck Surgery, University Hospital Bonn, Bonn, Germany
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A Multi-Institutional Study to Evaluate Automated Whole Slide Scoring of Immunohistochemistry for Assessment of Programmed Death-Ligand 1 (PD-L1) Expression in Non–Small Cell Lung Cancer. Appl Immunohistochem Mol Morphol 2019; 27:263-269. [DOI: 10.1097/pai.0000000000000737] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Yang H, Zhou X, Sun L, Mao Y. Correlation Between PD-L2 Expression and Clinical Outcome in Solid Cancer Patients: A Meta-Analysis. Front Oncol 2019; 9:47. [PMID: 30891423 PMCID: PMC6413700 DOI: 10.3389/fonc.2019.00047] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 01/17/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway are a paradigm-shifting cancer therapy. Programmed cell death ligand 2 (PD-L2) is another ligand of PD-1, but its prognostic significance in solid cancer patients after surgery remains controversial. In this study, we aimed to reveal the prognostic implication of PD-L2 in solid tumors through a meta-analysis. Methods: We searched PubMed, Embase and the Cochrane library for studies reporting the relationship between PD-L2 expression and prognosis or clinicopathological features in solid cancer patients after surgery from inception to January 2018, with language restricted to English. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were determined to explore the prognostic value of PD-L2 expression. Odds ratios (ORs) were also calculated to investigate the relationship between PD-L2 expression and clinicopathological parameters. Results: Sixteen studies incorporating 3,533 patients were included in our meta-analysis. The pooled results revealed that PD-L2 overexpression was a weak negative predictor for overall survival (OS; HR = 1.38, 95% CI = 1.05-1.81, P = 0.021), as well as a strong predictor for poor disease-free survival (DFS)/progression-free survival (PFS) (HR = 1.44, 95% CI = 1.15-1.81, P = 0.001). In subgroup analyses, high PD-L2 expression revealed an unfavorable prognostic prediction for OS in hepatocellular carcinoma (HCC) (HR = 1.60, 95% CI = 1.12-2.29, P = 0.011) and for DFS/PFS in HCC (HR = 1.50, 95%CI = 1.04-2.16, P = 0.031) as well as clear cell renal cell carcinoma (HR = 1.45, 95% CI = 1.03-2.03, P = 0.033). Moreover, PD-L2 expression implied a weak trend toward the presence of lymphatic metastasis (presence vs. absence, OR = 1.61, 95% CI = 0.98-2.65, P = 0.061). Conclusion: High PD-L2 expression may promote tumor metastasis and predict unfavorable prognosis in solid cancer patients after surgery, especially in HCC.
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Affiliation(s)
- Huayu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoxiang Zhou
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Lejia Sun
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, PUMC and Chinese Academy of Medical Sciences, Beijing, China
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From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer. Int J Mol Sci 2018; 20:ijms20010013. [PMID: 30577521 PMCID: PMC6337592 DOI: 10.3390/ijms20010013] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 12/15/2018] [Accepted: 12/17/2018] [Indexed: 12/24/2022] Open
Abstract
Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.
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Angell HK, Lee J, Kim KM, Kim K, Kim ST, Park SH, Kang WK, Sharpe A, Ogden J, Davenport A, Hodgson DR, Barrett JC, Kilgour E. PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. Oncoimmunology 2018; 8:e1544442. [PMID: 30729066 PMCID: PMC6351089 DOI: 10.1080/2162402x.2018.1544442] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 10/12/2018] [Accepted: 10/16/2018] [Indexed: 01/26/2023] Open
Abstract
This study investigates the association of PD-L1 expression and immune cell infiltrates and their impact on clinical outcome, in addition to their overlap with microsatellite instability (MSI), HER2 and ATM molecular subgroups of gastric cancer (GC). PD-L1 membrane expression on tumour cells (TC) and infiltrating immune cells (IC), CD3 + T-lymphocytes, CD8+ cytotoxic T-cells, ATM and HER2 were assessed by immunohistochemistry (IHC) in the ACRG (Asian Cancer Research Group) GC cohort (N = 380). EBV status was determined using in situ hybridization and MSI status was performed using PCR and MLH1 IHC. The PD-L1 segment was associated with increased T-cell infiltrates, while the MSI-high segment was enriched for PD-L1, CD3, and CD8. Multivariate analysis confirmed PD-L1 positivity, high CD3 and high CD8 as independent prognostic factors for both disease-free survival and overall survival (all p < 0.05). Patients with MSI-high tumours had better overall survival by both univariate and multivariate analysis. The ATM-low and HER2-high subgroups differed markedly in their immune profile; the ATM-low subgroups enriched for MSI, PD-L1 positivity and CD8 + T-cells, while the HER2 segment was enriched for MSS, with no enrichment for immune markers. Hence, we demonstrate a molecular profiling approach that can divide GC into four molecular subgroups, namely ATM-low, HER2-high, PD-L1 positive and MSI-high with differing levels of immune infiltrates and prognostic significance which may help to stratify patients for response to targeted therapies.
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Affiliation(s)
- H K Angell
- Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - J Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - K-M Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - K Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - S-T Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - S H Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - W K Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - A Sharpe
- Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - J Ogden
- Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - A Davenport
- Wythenshawe Hospital, Manchester Foundation Trust
| | - D R Hodgson
- Oncology, IMED Biotech Unit, AstraZeneca, Macclesfield, UK
| | - J C Barrett
- Oncology, IMED Biotech Unit, AstraZeneca, Boston, USA
| | - E Kilgour
- Oncology, IMED Biotech Unit, AstraZeneca, Macclesfield, UK
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