|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
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.
Collapse
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.
| | | | | |
Collapse
|
|
4
|
Wang X, Guo Z, Wu X, Chen D, Wang F, Yang L, Luo M, Wu S, Yang C, Huang L, Fu L. Predictive Nomogram for Hyperprogressive Disease During Anti-PD-1/PD-L1 Treatment in Patients with Advanced Non-Small Cell Lung Cancer. Immunotargets Ther 2023; 12:1-16. [PMID: 36632330 PMCID: PMC9828302 DOI: 10.2147/itt.s373866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/29/2022] [Indexed: 01/05/2023] Open
Abstract
Introduction Various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed. Methods This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated. Results Anti-PD-1/PD-L1 therapy resulted in a 9.66% (17/176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS: 7.00 vs 12.00 months, P<0.01; PFS: 2.00 vs 5.00 months, P<0.001, respectively). The HPD prediction nomogram included APTT (P<0.01), CD4+ CD25+ CD127-low cells (Treg cells) (P<0.01), the presence of liver metastasis (P<0.05), and more than two metastatic sites (P<0.05). Then, patients were divided into two groups by the "HPD score" calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%). Conclusions The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.
Collapse
Affiliation(s)
- Xueping Wang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Zhixing Guo
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Xingping Wu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Da Chen
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Fang Wang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Lewei Yang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Min Luo
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Shaocong Wu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Chuan Yang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Lamei Huang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China,Correspondence: Liwu Fu, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, 651 Dongfengdong Road, Guangzhou, 510060, People’s Republic of China, Email
| |
Collapse
|
|
5
|
Yuan L, Xu J, Shi Y, Jin Z, Bao Z, Yu P, Wang Y, Xia Y, Qin J, Zhang B, Yao Q. CD3D Is an Independent Prognostic Factor and Correlates With Immune Infiltration in Gastric Cancer. Front Oncol 2022; 12:913670. [PMID: 35719985 PMCID: PMC9198637 DOI: 10.3389/fonc.2022.913670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/27/2022] [Indexed: 12/20/2022] Open
Abstract
The protein encoded by CD3D is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. Previous studies have shown that CD3D is associated with prognosis and treatment response in breast, colorectal, and liver cancer. However, the expression and clinical significance of CD3D in gastric cancer are not clear. In this study, we collected 488 gastric cancer tissues and 430 paired adjacent tissues to perform tissue microarrays (TMAs). Then, immunohistochemical staining of CD3D, CD3, CD4, CD8 and PD-L1 was conducted to investigate the expression of CD3D in gastric cancer and the correlation between the expression of CD3D and tumor infiltrating lymphocytes (TILs) and PD-L1. The results showed that CD3D was highly expressed in gastric cancer tissues compared with paracancerous tissues (P<0.000). Univariate and multivariate analyses showed that CD3D was an independent good prognostic factor for gastric cancer (P=0.004, HR=0.677, 95%CI: 0.510-0.898 for univariate analyses; P=0.046, HR=0.687, 95%CI: 0.474-0.994 for multivariate analyses). In addition, CD3D was negatively correlated with the tumor location, Borrmann type and distant metastasis (P=0.012 for tumor location; P=0.007 for Borrmann type; P=0.027 for distant metastasis). In addition, the expression of CD3D was highly positively correlated with the expression of CD3, CD4, CD8, and PD-L1, and the combination of CD3D with CD3, CD4, CD8 and PD-L1 predicted the best prognosis (P=0.043). In summary, CD3D may play an important regulatory role in the tumor immune microenvironment of gastric cancer and may serve as a potential indicator of prognosis and immunotherapy response.
Collapse
Affiliation(s)
- Li Yuan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China.,Zhejiang Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jingli Xu
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yunfu Shi
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhiyuan Jin
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zhehan Bao
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Pengcheng Yu
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yi Wang
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuhang Xia
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiangjiang Qin
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, China.,Zhejiang Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Bo Zhang
- Department of Integrated Chinese and Western Medicine, Institute of Basic Medicine and Cancer (IBMC), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou, China
| | - Qinghua Yao
- Department of Integrated Chinese and Western Medicine, Institute of Basic Medicine and Cancer (IBMC), The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Chinese Academy of Sciences, Hangzhou, China.,Key Laboratory of Traditional Chinese Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China.,Key Laboratory of Head and Neck Cancer Translational Research of Zhejiang Province, Hangzhou, China
| |
Collapse
|
|
6
|
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).
Collapse
|
|
7
|
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: 827] [Impact Index Per Article: 206.8] [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.
Collapse
|
|
8
|
Wei XL, Luo X, Sheng H, Wang Y, Chen DL, Li JN, Wang FH, Xu RH. PD-L1 expression in liver metastasis: its clinical significance and discordance with primary tumor in colorectal cancer. J Transl Med 2020; 18:475. [PMID: 33308232 PMCID: PMC7730753 DOI: 10.1186/s12967-020-02636-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/27/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The outcomes of immune checkpoint inhibitors in cancer patients with liver metastases are poor, which may be related to a different tumor microenvironment in liver metastases from primary tumors. This study was aimed to analyze PD-L1 expression and the immune microenvironment status in liver metastases and compare the differences of PD-L1 expression between primary tumors and liver metastases of colorectal cancer. METHODS 74 cases of pathologically confirmed colorectal cancer with liver metastasis underwent resection from our hospital were included. Tissue microarrays were used for the interpretation of PD-L1 expression, cluster of differentiation 4 (CD4) and CD8 density by immunohistochemistry. We evaluated the disparity between primary tumor and liver metastasis in PD-L1 expression, CD4 and CD8 density and analyzed the factors associated with obvious PD-L1 disparity. RESULTS The expression of PD-L1 was positively related to the density of CD4 and CD8 in liver metastases. The expression of PD-L1 in liver metastases was higher than in primary tumors in certain subgroups, including patients with concurrent liver metastases (n = 63, p = 0.05), patients receiving concurrent resection of primary and metastatic tumors (n = 56, p = 0.04). The two subgroups generally reflected those without inconsistent external influences, such as treatment and temporal factors, between primary tumors and liver metastases. In these subgroups, the intrinsic differences of microenvironment between primary tumors and liver metastases could be identified. Furthermore, tumor differentiation [moderate vs. poor: OR = 0.23, 95% CI: 0.03-0.99, p = 0.05)] were demonstrated to be associated with obvious discordance of PD-L1 expression between primary tumors and liver metastases. CONCLUSIONS The expression of PD-L1 in liver metastases was higher than in primary tumors in subgroups, reflecting intrinsic microenvironment differences between primary and metastatic tumors. Obvious discordance of PD-L1 expression between primary tumor and liver metastasis was significantly related to the tumor differentiation.
Collapse
Affiliation(s)
- Xiao-Li Wei
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, China
| | - Xuan Luo
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Hui Sheng
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Yun Wang
- Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Dong-Liang Chen
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, China
| | - Jia-Ning Li
- Department of Clinical Trial Center, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, China.
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, China.
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, China.
| |
Collapse
|
|
9
|
Polasky C, Wendt F, Pries R, Wollenberg B. Platelet Induced Functional Alteration of CD4 + and CD8 + T Cells in HNSCC. Int J Mol Sci 2020; 21:ijms21207507. [PMID: 33053760 PMCID: PMC7588893 DOI: 10.3390/ijms21207507] [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: 08/26/2020] [Revised: 10/09/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022] Open
Abstract
Platelets (PLT) are the second most abundant cell type in human blood and exert various immune-regulatory functions under both physiological and pathological conditions. In fact, immune cell regulation via platelets has been demonstrated in several studies within the past decade. However, the exact mechanisms behind T cell regulation remain poorly understood. We questioned whether the formation of aggregates of platelets and T cells has an impact on T-cell functions. In the present study, we stimulated PBMC cultures with anti-CD3 and anti-CD28 mABs and cultured them at a PLT: PBMC ratio of 1:1 or 100:1. After 24, 48, and 72 h, PD-1, PD-L1 expression, and proliferation were analyzed on T cells using flow cytometry. Cytokine production was measured in PHA stimulated CD4 cells after 6 h. We found a significant platelet-mediated decrease in PD-1 and PD-L1 expression, proliferation, as well as IFN-γ and TNF-α production. Perturbations also at least partially remained after spatial separation of PLTs from PBMCs in Transwell-assays. T cell-platelet aggregates showed similar levels of activation markers, proliferation, and secreted cytokines as their non-complexed counterparts. Results indicate a platelet mediated regulation of T cells via direct and indirect contact, but only mediocre effects of the complex formation itself.
Collapse
Affiliation(s)
- Christina Polasky
- Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany; (F.W.); (R.P.)
- Correspondence: ; Tel.: +49-451-500-42129
| | - Franziska Wendt
- Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany; (F.W.); (R.P.)
| | - Ralph Pries
- Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany; (F.W.); (R.P.)
| | - Barbara Wollenberg
- Department of Otorhinolaryngology, University Hospital MRI, Technical University, 81675 München, Germany;
| |
Collapse
|
|
10
|
Profiles of PD-1, PD-L1, PD-L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2496582. [PMID: 32596285 PMCID: PMC7298268 DOI: 10.1155/2020/2496582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022]
Abstract
Background Although multiple types of cancers demonstrated favorable outcome after immunotherapy of PD-1/PD-L1 blockade, the specific regulatory mechanism of PD genes in gastric cancer (GC) remains largely unknown. Materials and Methods Expression of RNA, copy number variants, and clinical parameters of GC individuals from TCGA were analyzed. Coexpressed genes for PD-1, PD-L1, and PD-L2 were selected by correlation analysis and confirmed by STRING. Gene Ontology and KEGG pathway analyses were performed by clusterProfiler. The influence of PD-1/PD-L1/PD-L2 on immune cell infiltration was investigated by MCP-counter. Results PD-L2 demonstrated significant relation with clinical stage of GC (P = 0.043). Survival analysis showed that PD-1 expression was correlated with better prognosis of GC patients (HR = 0.70, P = 0.031), but PD-L2 expression was related with worse survival (HR = 1.42, P = 0.032). Mutation of PIK3CA could alter the level of PD-1, PD-L1, and PD-L2 (P < 0.001), and TP53 mutation demonstrated significant correlation with PD-L1 (P = 0.015) and PD-L2 (P = 0.014) expression. Enrichment analysis of PD-1/PD-L1/PD-L2 coexpressed genes indicated a biological process of mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1 and Th2, cell differentiation of Th17, and hematopoietic cell landscape. As for immune infiltration analysis, PD-1 was mainly related with cytotoxic lymphocytes and endothelial cells; PD-L1 were associated with monocytic lineage; PD-L2 showed significant correlation with myeloid dendritic cells. Conclusion PD-1 expression showed association with better prognosis of GC, and PD-L2 expression was related with worse survival. Mutations of PIK3CA and TP53 significantly correlated with PD-1/PD-L1/PD-L2 axis. PD-1/PD-L1/PD-L2 coexpressed genes demonstrated enrichment in mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1, Th2, and Th17.
Collapse
|
|
11
|
Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2. Mol Immunol 2020; 124:35-41. [PMID: 32512320 DOI: 10.1016/j.molimm.2020.05.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Bladder cancer (BC) can be successfully treated by manipulating immune responses with intravesical Bacillus Calmette-Guerin instillation or targeting the PD-1/PD-L signaling pathway. In the present study we investigated the prognostic significance of the immune checkpoint inhibitor PD-1 and its ligands PD-L1 and PD-L2 on tumor cells and infiltrating lymphocytes, in the tumor microenvironment and draining lymph nodes in patients with non-metastatic BC. PATIENTS AND METHODS Cells were mechanically isolated from tissues and draining lymph nodes from 58 patients, and surface-stained for CD45, PD-1, PD-L1 and PD-L2. The cells were then analyzed with a flow cytometric method. RESULTS Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival. CONCLUSION Our results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.
Collapse
|
|
12
|
Kim JH, Kim K, Kim M, Kim YM, Suh JH, Cha HJ, Choi HJ. Programmed death-ligand 1 expression and its correlation with clinicopathological parameters in gallbladder cancer. J Pathol Transl Med 2020; 54:154-164. [PMID: 32028754 PMCID: PMC7093290 DOI: 10.4132/jptm.2019.11.13] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/12/2019] [Indexed: 01/15/2023] Open
Abstract
Background Immunomodulatory therapies targeting the interaction between programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) have become increasingly important in anticancer treatment. Previous research on the subject of this immune response has established an association with tumor aggressiveness and a poor prognosis in certain cancers. Currently, scant information is available on the relationship between PD-L1 expression and gallbladder cancer (GBC). Methods We investigated the expression of PD-L1 in 101 primary GBC cases to determine the potential association with prognostic impact. PD-L1 expression was immunohistochemically assessed using a single PD-L1 antibody (clone SP263). Correlations with clinicopathological parameters, overall survival (OS), or progression- free survival (PFS) were analyzed. Results PD-L1 expression in tumor cells at cutoff levels of 1%, 10%, and 50% was present in 18.8%, 13.8%, and 7.9% of cases. Our study showed that positive PD-L1 expression at any cutoff was significantly correlated with poorly differentiated histologic grade and the presence of lymphovascular invasion (p < .05). PD-L1 expression at cutoff levels of 10% and 50% was significantly positive in patients with perineural invasion, higher T categories, and higher pathologic stages (p < .05). Additionally, there was a significant association noted between PD-L1 expression at a cutoff level of 50% and worse OS or PFS (p = .049 for OS, p = .028 for PFS). Other poor prognostic factors included histologic grade, T category, N category, pathologic stage, lymphovascular invasion, perineural invasion, growth pattern, and margin of resection (p < .05). Conclusions The expression of PD-L1 in GBC varies according to cutoff level but is valuably associated with poor prognostic parameters and survival. Our study indicates that the overexpression of PD-L1 in GBC had a negative prognostic impact.
Collapse
Affiliation(s)
- Ji Hye Kim
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea
| | - Kyungbin Kim
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea
| | - Misung Kim
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea
| | - Young Min Kim
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea.,University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae Hee Suh
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea.,University of Ulsan College of Medicine, Ulsan, Korea
| | - Hee Jeong Cha
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea.,University of Ulsan College of Medicine, Ulsan, Korea
| | - Hye Jeong Choi
- Department of Pathology, Ulsan University Hospital, Ulsan, Korea.,University of Ulsan College of Medicine, Ulsan, Korea
| |
Collapse
|
|
13
|
Lu J, Xu Y, Wu Y, Huang XY, Xie JW, Wang JB, Lin JX, Li P, Zheng CH, Huang AM, Huang CM. Tumor-infiltrating CD8+ T cells combined with tumor-associated CD68+ macrophages predict postoperative prognosis and adjuvant chemotherapy benefit in resected gastric cancer. BMC Cancer 2019; 19:920. [PMID: 31521128 PMCID: PMC6744628 DOI: 10.1186/s12885-019-6089-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 08/26/2019] [Indexed: 01/08/2023] Open
Abstract
Background Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Methods Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. Results Compared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank p<0.001; multivariate HR: 0.372; 95% confidence interval (CI): 0.239–0.579, p<0.001]. In contrast, compared with CD68+ TAM-negative cases (n = 217, 54.1%), CD68+ TAM-positive cases (n = 184, 45.9%) had significantly poor RFS [log-rank p<0.001; multivariate HR: 2.182; 95% CI: 1.435–3.318, p<0.001]. Thus, patients with a positive CD8+ TIL and negative CD68+ TAM status exhibited significantly increased RFS. Multivariate analysis demonstrated that CD8+ TILs and CD68+ TAMs may serve as independent prognostic markers for RFS. Incorporating CD8+ TIL and CD68+ TAM statuses into the AJCC TNM system generated a predictive model with better predictive accuracy for RFS. More importantly, patients with a positive TIL and negative TAM status showed a tendency of improved RFS after postoperative adjuvant chemotherapy (PAC). Similar results were obtained by overall survival (OS) analysis. Conclusions CD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC. Trial registration The current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481) on December 30, 2014. Electronic supplementary material The online version of this article (10.1186/s12885-019-6089-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Yu Xu
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,lnstitue of Oncology of Fujian Medical University, Fuzhou, China
| | - Yuan Wu
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,lnstitue of Oncology of Fujian Medical University, Fuzhou, China
| | - Xiao-Yan Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
| | - Ai-Min Huang
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. .,lnstitue of Oncology of Fujian Medical University, Fuzhou, China.
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
| |
Collapse
|
|
14
|
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.
Collapse
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
| |
Collapse
|
|
15
|
Liu Y, Shao C, Zhu L, Jiang S, Li G, Zhang W, Lin Y, Ni Y, Cao H, Shao S. High Expression of ABL2 Suppresses Apoptosis in Gastric Cancer. Dig Dis Sci 2018; 63:2294-2300. [PMID: 29767389 DOI: 10.1007/s10620-018-5111-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 05/04/2018] [Indexed: 12/09/2022]
Abstract
BACKGROUND Diseases associated with Abelson-related gene (also called ABL2) include leukemia; furthermore, previous researches have studied the expressions and functions of ABL2 in different types of malignancies and found that it plays an important role in almost all kinds of cancers. AIMS Nevertheless, the mechanism of ABL2 in gastric cancer (GC) remains vague. METHODS In the present study, the level of ABL2 in human GC tissues was detected by immunohistochemistry. Also, the GC cell lines MGC-803 and BGC-823 were selected to stably knock down and overexpress the level of ABL2 by corresponding lentiviral vectors. Puromycin was used to maintain the stable low expression of ABL2 MGC-803 cells compared with control cells; what is more, the high expression of ABL2 BGC-823 cells was also obtained. Based on it, we detected the proteins associated with apoptosis, such as Bcl-2 family and caspase family by western blotting. RESULTS The most appropriate concentration of puromycin to kill GC cells is 1 µg/mL; then, we obtained the corresponding stable cell lines. Furthermore, we found that high level of ABL2 in BGC-823 cells increased the expression of Bcl-XL, total PARP, and caspase3, while decreased the level of cleaved caspase3 and cleaved caspase9. Consistent results are received in MGC-803 cells. In addition, ABL2 overexpression led to the protein related with Ras/Erk and PI3K/AKT signaling pathway increased; also, we found that the major proteins play a significant role in it. CONCLUSION All the data showed that high expression of ABL2 suppresses apoptosis through Ras/Erk and PI3K/AKT signaling pathway in GC cell lines.
Collapse
Affiliation(s)
- Yun Liu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Linqi Zhu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Sihong Jiang
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Guanlin Li
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Wei Zhang
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Yajing Lin
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Ying Ni
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Hui Cao
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Shihe Shao
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
| |
Collapse
|
|
16
|
Lazăr DC, Avram MF, Romoșan I, Cornianu M, Tăban S, Goldiș A. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer. World J Gastroenterol 2018; 24:3583-3616. [PMID: 30166856 PMCID: PMC6113718 DOI: 10.3748/wjg.v24.i32.3583] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/05/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with different clinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.
Collapse
Affiliation(s)
- Daniela Cornelia Lazăr
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Ioan Romoșan
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mărioara Cornianu
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Sorina Tăban
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Adrian Goldiș
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| |
Collapse
|
|
17
|
Shi B, Li Q, Ma X, Gao Q, Li L, Chu J. High expression of programmed cell death protein 1 on peripheral blood T-cell subsets is associated with poor prognosis in metastatic gastric cancer. Oncol Lett 2018; 16:4448-4454. [PMID: 30214579 PMCID: PMC6126159 DOI: 10.3892/ol.2018.9190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 05/24/2018] [Indexed: 12/16/2022] Open
Abstract
Immune checkpoints in solid tumors serve important roles in metastasis. The present study was designed to explore the expression of programmed cell death protein 1 (PD-1) on peripheral blood T-cell subsets and its role in the clinicopathological features and prognosis of patients with metastatic gastric cancer. The expression of PD-1 in peripheral blood T-cell subsets was detected in 100 metastatic gastric cancer patients prior to the first line chemotherapy by flow cytometric analysis. The potential associaton between the peripheral blood T-cell subsets PD-1 level and the clinicopathological features of patients with metastatic gastric cancer and the clinical outcomes was analyzed. The percent of high PD-1 expressed cluster of differentiation (CD)3+, CD3+CD4+ and CD3+CD8+ T-cells was 20.4, 13.0 and 9.4%, respectively in patients with metastatic gastric cancer. The overall survival (OS) and progression-free survival (PFS) rate of the 100 patients with metastatic gastric cancer was 12.2 and 3.9 months, respectively. Kaplan-Meier curve with long-rank analysis indicated that patients with higher PD-1+/CD3+, PD-1+/CD3+CD4+ and PD-1+/CD3+CD8+ levels had a worse prognosis (all P<0.05). Univariate and multivariate analysis revealed that high PD-1+/CD3+ [hazard ratio (HR), 2.145; P=0.015], high PD-1+/CD3+CD4+ (HR, 1.866; P=0.034) and high PD-1+/CD3+CD8+ (HR, 1.817; P=0.033) level in peripheral blood were independent risk factors for predicting the survival time of patients with metastatic gastric cancer. High PD-1+/CD3+, high PD-1+/CD3+CD4+ and high PD-1+/CD3+CD8+ expression conferred a lower overall survival rate in patients with metastatic gastric cancer. These results suggest that high PD-1 expression on peripheral blood T-cell subsets may potentially be novel prognostic biomarker for metastatic gastric cancer.
Collapse
Affiliation(s)
- Bian Shi
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Qiujian Li
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Xuhui Ma
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Qilong Gao
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Lu Li
- Department of Integrated Traditional Chinese and Western Medical Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| | - Junfeng Chu
- Department of Oncology, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, Henan 450001, P.R. China
| |
Collapse
|
|
18
|
Gkolfinopoulos S, Papamichael D, Papadimitriou K, Papanastasopoulos P, Vassiliou V, Kountourakis P. Advances in molecular, genetic and immune signatures of gastric cancer: Are we ready to apply them in our patients' decision making? World J Gastrointest Oncol 2018; 10:172-183. [PMID: 30079143 PMCID: PMC6068857 DOI: 10.4251/wjgo.v10.i7.172] [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: 03/28/2018] [Revised: 05/16/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
In the last few years we have witnessed a vast expansion of our knowledge regarding the molecular and genetic profile of gastric cancer. The molecular subtypes described have shed light on the pathogenesis of the disease, thus prompting the development of new therapeutic strategies and favoring a more individualized approach for treatment. Most of the clinical trials for so called targeted therapies could be considered, at best, partially successful. In addition, checkpoint inhibitors have recently been added to our armamentarium in later stages of the disease, and combinations with chemotherapy and targeted agents are currently under development. In view of the rapid advances of molecular oncology, a new challenge for the clinical oncologist arises: The appropriate patient selection for each new therapy, which can be made possible only through the implementation of predictive biomarkers in our therapy decision making.
Collapse
|
|
19
|
Neyaz A, Husain N, Kumari S, Gupta S, Shukla S, Arshad S, Anand N, Chaturvedi A. Clinical relevance of PD-L1 expression in gallbladder cancer: a potential target for therapy. Histopathology 2018; 73:622-633. [DOI: 10.1111/his.13669] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 06/06/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Azfar Neyaz
- Department of Pathology; Dr Ram Manohar Lohia Institute of Medical Sciences; Lucknow India
| | - Nuzhat Husain
- Department of Pathology; Dr Ram Manohar Lohia Institute of Medical Sciences; Lucknow India
| | - Swati Kumari
- Department of Pathology; Dr Ram Manohar Lohia Institute of Medical Sciences; Lucknow India
| | - Sameer Gupta
- Department of Surgical Oncology; King George's Medical University; Lucknow India
| | - Saumya Shukla
- Department of Pathology; Dr Ram Manohar Lohia Institute of Medical Sciences; Lucknow India
| | - Sanya Arshad
- Department of Pathology; Dr Ram Manohar Lohia Institute of Medical Sciences; Lucknow India
| | - Nidhi Anand
- Department of Pathology; Dr Ram Manohar Lohia Institute of Medical Sciences; Lucknow India
| | - Arun Chaturvedi
- Department of Surgical Oncology; King George's Medical University; Lucknow India
| |
Collapse
|
|
20
|
Zhuang W, Ma J, Chen X, Wang G, Lu J, Chen Y, Dong H, Cai S, Zhang Y, Zhao X, Zhu Y, Xu C, Huang Y, Huang Z, Zhu X, Jiang H, Wang Z. The Tumor Mutational Burden of Chinese Advanced Cancer Patients Estimated by a 381-cancer-gene Panel. J Cancer 2018; 9:2302-2307. [PMID: 30026825 PMCID: PMC6036723 DOI: 10.7150/jca.24932] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 04/02/2018] [Indexed: 12/30/2022] Open
Abstract
Purpose: Tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is proved to be effective to predict the clinical benefit of immune checkpoint blockades. However, WES is not commonly used in China. We aimed to determine if a 381-caner-gene panel (CGP) could be used to estimate TMB, delineate the landscape of TMB of Chinese patients and identify mutated genes and pathways related to higher TMB. Methods: We first evaluated the correlation between the TMB estimated by a 381-cancer-gene panel MasterView and WES using the data from the melanoma sample cohort. 3023 formalin fixed, paraffin-embedded tumor specimens from 2932 Chinese patients with advanced solid tumor were profiled for 381 gene sequencing, the baits of which covered 4,557 exons of 365 cancer-related genes and 47 introns of 25 genes frequently rearranged in cancer (All performed in a lab who achieved full marks five times in the external quality assessment by College of American Pathologists [CAP]). Using the sequencing data, we estimated the TMB of Chinese advanced solid tumor and identified mutated genes and pathways related to higher TMB level. Results: 381-CGP-mutational burden was strongly associated with those calculated by WES (R2 = 0.978). The median TMB for each tumor type was 5.65 (colorectal cancer), 4.84 (lung cancer), 4.03 (hepatobiliary cancer), 4.03 (gastric carcinoma), 4.03 (breast cancer) mutations/mb respectively. No correlation was observed between TMB level and age (P = 0.577) or gender (P = 0.307). The TMB of patients with mismatch repair (MMR) or DNA repair response (DDR) pathway deficiency was significantly higher than that without MMR or DDR pathway deficiency (P < 0.001). Conclusion: The 381-cancer gene panel is a clinical practicable method to assess tumor mutational burden compared with whole exome sequencing. MMR and DDR deficiency are correlated with higher tumor mutational burden of Chinese patients with advanced solid tumors.
Collapse
Affiliation(s)
- Wu Zhuang
- Department of Medical Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fujian, P.R. China
| | - Junxun Ma
- Department of Oncology, Chinese PLA General Hospital, Beijing, P.R. China
| | - Xudong Chen
- Department of Interventional Radiology, the Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, P.R. China
| | - Guoqiang Wang
- The medical department, 3D Medicine Inc. Shanghai, P.R. China
| | - Jing Lu
- The bioinformatics department, 3D Medicine Inc. Shanghai, P.R. China
| | - Yanan Chen
- The bioinformatics department, 3D Medicine Inc. Shanghai, P.R. China
| | - Hua Dong
- The bioinformatics department, 3D Medicine Inc. Shanghai, P.R. China
| | - Shangli Cai
- The medical department, 3D Medicine Inc. Shanghai, P.R. China
| | - Yuzi Zhang
- The medical department, 3D Medicine Inc. Shanghai, P.R. China
| | - Xiaochen Zhao
- The medical department, 3D Medicine Inc. Shanghai, P.R. China
| | - Youcai Zhu
- Department of Thoracic Disease Center, Zhejiang Rongjun Hospital, Zhejiang, P.R. China
| | - Chunwei Xu
- Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fujian, P.R. China
| | - Yunjian Huang
- Department of Medical Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fujian, P.R. China
| | - Zhangzhou Huang
- Department of Medical Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fujian, P.R. China
| | - Xiaofeng Zhu
- Transplantation Center, Department of Transplant Surgery, The First Affiliated Hospital, Sun Yet-sen University, Guangzhou, P. R. China
| | - Hong Jiang
- Oncology Department, East Hospital Affiliated to Shanghai Tongji University, Shanghai, P.R. China
| | - Zhijie Wang
- Department of medical oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, P.R. China
| |
Collapse
|
|
21
|
Wang L, Zhang Q, Ni S, Tan C, Cai X, Huang D, Sheng W. Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status. Cancer Med 2018; 7:2612-2620. [PMID: 29673110 PMCID: PMC6010739 DOI: 10.1002/cam4.1502] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies. Immunotherapy is a promising targeted treatment. The immune regulatory programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has been used as a checkpoint target for immunotherapy. Currently, considerable discrepancies exist concerning the expression status of PD-L1 and its prognostic value in GC. We aimed to evaluate the expression rates of PD-L1 in GC, and further assess its relationship with mismatch repair (MMR), and human epidermal growth factor receptor 2 (HER2) status. We retrospectively collected 550 consecutive cases of GC in Fudan University Shanghai Cancer Center from 2010 to 2012. PD-L1, MMR protein, and HER2 status were detected by immunohistochemistry (IHC). Fluorescence in situ hybridization was further used in HER2 IHC 2+ cases. Cases with at least 1% membranous and/or cytoplasmic PD-L1 staining in either tumor cells (TCs) or tumor-infiltrating immune cells (TIICs) were considered as PD-L1 positive. The correlation between clinicopathological parameters, HER2, MMR, and PD-L1 expression status was determined using chi-squared tests. About 37.3% cases (205/550) showed PD-L1 expression in TCs and/or TIICs. 17.3% cases (95/550) showed PD-L1 expression in TCs, 34.5% (190/550) cases showed PD-L1 expression in TIICs. There were 45 deficient MMR (dMMR) cases (8.2%), which showed higher rates of PD-L1 expression compared with MMR-proficient carcinomas (60.0% vs. 35.2%, P = 0.001). HER2 was positive in 66 (12.0%) cases. The expression of PD-L1 occurred more frequently in HER2-negative group than HER2-positive cohorts (39.0% vs. 24.2%, P = 0.020). The survival analysis revealed that PD-L1 was not associated with prognosis. This study evaluated the association between the PD-L1 expression and a specific subgroup (dMMR and HER2-negative) in a large Asian cohort of GC. GC patients with dMMR and HER2-negative status exhibited higher PD-L1 expression rates. Our finding indicated that MMR and HER-2 status might be potential biomarkers for anti-PD-L1 therapy.
Collapse
Affiliation(s)
- Lei Wang
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Qiongyan Zhang
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Shujuan Ni
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Cong Tan
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Xu Cai
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Dan Huang
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Weiqi Sheng
- Department of PathologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| |
Collapse
|
|
22
|
Kim Y, Wen X, Cho NY, Kang GH. Intratumoral immune cells expressing PD-1/PD-L1 and their prognostic implications in cancer: a meta-analysis. Int J Biol Markers 2018; 33:1724600818770941. [PMID: 29779430 DOI: 10.1177/1724600818770941] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The prognostic value of immune cells expressing programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) in cancer are controversial, and the potential differential impact of using tissue microarrays and whole tissue sections to assess the positivity of immune cells has not been addressed. METHODS The current study included 30 eligible studies with 7251 patients that evaluated the relationship between tumor-infiltrating lymphocytes expressing PD-1/PD-L1 and overall survival and disease-free survival, or progression-free survival. Subgroup analysis was based on the tissue type of cancer and the type of tissue sampling (tissue microarray or whole tissue section). RESULTS In the meta-analysis, PD-1-positive and PD-L1-positive tumor-infiltrating lymphocytes had a positive effect on disease-free survival or progression-free survival (hazard ratio [HR] 0.732; 95% confidence interval [CI] 0.565, 0.947; and HR 0.727; 95% CI 0.584, 0.905, respectively). PD-L1-positive tumor-infiltrating lymphocytes had a positive impact on overall survival in studies using tissue microarray (HR 0.586; 95% CI 0.476, 0.721), but had a poor impact when only whole tissue sections were considered (HR 1.558; 95% CI 1.232, 1.969). Lung cancer was associated with good overall survival and disease-free survival (HR 0.639; 95% CI 0.491, 0.831; and HR 0.693; 95% CI 0.538, 0.891, respectively) for PD-1-positive tumor-infiltrating lymphocytes, and colorectal cancer showed favorable disease-free survival (HR 0.471; 95% CI 0.308, 0.722) for PD-L1-positive tumor-infiltrating lymphocytes. CONCLUSION Immune cells expressing PD-1 and PD-L1 within tumors are associated with the prognosis. However, the correlation may vary among different tumor types and by the type of tissue sampling used for the assessment.
Collapse
Affiliation(s)
- Younghoon Kim
- 1 Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- 2 Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Xianyu Wen
- 1 Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- 2 Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Nam Yun Cho
- 1 Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Gyeong Hoon Kang
- 1 Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- 2 Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| |
Collapse
|
|
23
|
Pereira MA, Ramos MFKP, Faraj SF, Dias AR, Yagi OK, Zilberstein B, Cecconello I, Alves VAF, de Mello ES, Ribeiro U. Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer. J Surg Oncol 2018. [PMID: 29534305 DOI: 10.1002/jso.25022] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVES Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis. METHODS We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray. RESULTS EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes. CONCLUSION EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.
Collapse
Affiliation(s)
| | | | - Sheila F Faraj
- Cancer Institute, University of Sao Paulo, Sao Paulo, Brazil
| | - Andre R Dias
- Cancer Institute, University of Sao Paulo, Sao Paulo, Brazil
| | - Osmar K Yagi
- Cancer Institute, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Ivan Cecconello
- Cancer Institute, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | - Ulysses Ribeiro
- Cancer Institute, University of Sao Paulo, Sao Paulo, Brazil
| |
Collapse
|
|
24
|
Centonze M, Saponaro C, Mangia A. NHERF1 Between Promises and Hopes: Overview on Cancer and Prospective Openings. Transl Oncol 2018; 11:374-390. [PMID: 29455084 PMCID: PMC5852411 DOI: 10.1016/j.tranon.2018.01.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/02/2018] [Accepted: 01/05/2018] [Indexed: 02/07/2023] Open
Abstract
Na+/H+ exchanger regulatory factor 1 (NHERF1) is a scaffold protein, with two tandem PDZ domains and a carboxyl-terminal ezrin-binding (EB) region. This particular sticky structure is responsible for its interaction with different molecules to form multi-complexes that have a pivotal role in a lot of diseases. In particular, its involvement during carcinogenesis and cancer progression has been deeply analyzed in different tumors. The role of NHERF1 is not unique in cancer; its activity is connected to its subcellular localization. The literature data suggest that NHERF1 could be a new prognostic/predictive biomarker from breast cancer to hematological cancers. Furthermore, the high potential of this molecule as therapeutical target in different carcinomas is a new challenge for precision medicine. These evidences are part of a future view to improving patient clinical management, which should allow different tumor phenotypes to be treated with tailored therapies. This article reviews the biology of NHERF1, its engagement in different signal pathways and its involvement in different cancers, with a specific focus on breast cancer. It also considers NHERF1 potential role during inflammation related to most human cancers, designating new perspectives in the study of this "Janus-like" protein.
Collapse
Affiliation(s)
- Matteo Centonze
- Functional Biomorphology Laboratory, IRCCS-Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Concetta Saponaro
- Functional Biomorphology Laboratory, IRCCS-Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Anita Mangia
- Functional Biomorphology Laboratory, IRCCS-Istituto Tumori "Giovanni Paolo II", Bari, Italy.
| |
Collapse
|