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Expression and clinical value of programmed cell death-ligand 1(PD-L1)in diffuse large B cell lymphoma:a retrospective study

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Chinese Journal of Cancer 2017年第12期36卷 767-777页

作者： Li-Yang Hu Xiao-Lu Xu Hui-Lan Rao Jie Chen Ren-Chun Lai Hui-Qiang Huang Wen-Qi Jiang Tong-Yu Lin Zhong-Jun Xia Qing-Qing Cai State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Medical Oncology The Fifth Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 519000GuangdongP.R.China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology Guangzhou 510120GuangdongP.R.China Department of Radiotherapy Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou 510120GuangdongP.R.China Department of Anesthesiology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Hematology Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China

Background: The programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses.Diffuse large B-cell lymphoma(DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis.Methods: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical(IHC) assay. The expression of anaplastic lymphoma kinase(ALK), CD5,CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus(EBV)-encoded RNAs(EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis.Results: Of the 204 patients, 100(49.0%) were PD-L1-positive in tumor cells and 44(21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like(GCB) subtype than in the GCB subtype(P = 0.02 and P= 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment(P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression(r =-0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival(OS)rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells(P = 0.02). PD-L1 expression in tumor cells was an

关键词： Programmed cell death-ligand 1 (PD-L1) Diffuse large B-cell lymphoma C-Myc Prognosis

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Prognostic value of programmed death.1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1.4N+M0 gastric adenocarcinoma

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Chinese Journal of Cancer 2017年第11期36卷 560-573页

作者： Yuan Gao Su Li Dazhi Xu Shangxiang Chen Yuchen Cai Wenqi Jiang Xinke Zhang Jin Sun Kefeng Wang Boyang Chang Fenghua Wang Minghuang Hong Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060GuangdongP.R.China Department of Clinical Trial Center Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Gastric Surgery Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China Department of Image‑guided Minimally Invasive Therapy Sun Yat-sen University Cancer CenterGuangzhou 510060GuangdongP.R.China.

Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with

关键词： Gastric cancer Programmed cell death-ligand 1 Programmed cell death-ligand 2 Programmed cell death-1 CD8(+) T cells Heterogeneity expression Prognostic value

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Anti program death-1/anti program death-ligand 1 in digestive cancers

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World Journal of Gastrointestinal Oncology 2015年第8期7卷 95-101页

作者： Eléonore de Guillebon Pauline Roussille Eric Frouin David Tougeron Medical Oncology Department Poitiers University Hospital Radiation Oncology Department Poitiers University Hospital Pathology Department Poitiers University Hospital David Tougeron Laboratory Inflammation Tissus Epithéliaux et Cytokines EA 4331 Poitiers University Gastroenterology Department Poitiers University Hospital

Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1(PD-1) and program death-ligand 1(PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies(m Abs), called immune checkpoint inhibitors(ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1(nivolumab, pembrolizumab) and anti-PD-L1 m Abs(MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase Ⅱ will start soon. In metastatic colorectal cancer(CRC), a phase Ⅲ trial of MPDL3280 A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration(i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection ofpatients likely to benefit from ICIs.

关键词： Program death-1 Program death-ligand 1 Antibody Digestive cancer

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Cdk5 knocking out mediated by CRISPR-Cas9 genome editing for PD-L1 attenuation and enhanced antitumor immunity

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Acta Pharmaceutica Sinica B 2020年第2期10卷 358-373页

作者： Huan Deng Songwei Tan Xueqin Gao Chenming Zou Chenfeng Xu Kun Tu Qingle Song Fengjuan Fan Wei Huang Zhiping Zhang School of Pharmacy Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Institute of Hematology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China National Engineering Research Center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering Research Center for Novel Drug Delivery System Huazhong University of Science and TechnologyWuhan 430030China

Blocking the programmed death-ligand 1(PD-L1)on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy.However,only a minority of patients presented immune responses in clinical trials.To develop an alternative treatment method based on immune checkpoint blockade,we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells via specifically knocking out Cyclin-dependent kinase 5(Cdk5)gene in vivo.The expression of PD-L1 on tumor cells was significantly attenuated by knocking out Cdk5,leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer.Importantly,we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8^+T cells was significantly increased while regulatory T cells(Tregs)was decreased.It may be the first case to exhibit direct in vivo PD-L1 downregulation via CRISPR-Cas9 genome editing technology for cancer therapy.It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.

关键词： CRISPR-Cas9 genome editing system Cyclin-dependent kinase 5(Cdk5) Programmed death-ligand 1(PD-L1) Antitumor immunity Nanoparticles

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PD-1/PD-L1 antagonists in gastric cancer:Current studies and perspectives

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World Journal of Meta-Analysis 2019年第3期7卷 101-109页

作者： Jian Li Xiao-Hong Zhang Song-Hua Bei Li Feng Endoscopy Center Minhang Branch of Zhongshan HospitalFudan University

Immune checkpoints release suppressive signals for T cells,which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors.At present,programmed death receptor 1(PD-1)/programmed death ligand-1(PDL1) has become the most promising therapeutic target.PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers,such as melanoma and non-small-cell lung cancer.Moreover,PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer,and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool.Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer.Furthermore,there are many molecules involved in the regulation of PD-1/PD-L1 expression,and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer.In this review,the efficacy,safety,and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.

关键词： Immunotherapy PD-1/PD-L1 inhibitors Programmed death-ligand 1 Gastric cancer

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抗PD-L1治疗在大鼠淋巴管畸形模型中的作用

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口腔医学研究 2020年第4期36卷 328-332页

作者：姜浩钟文群邹艳平李雪丛蔡育武汉大学口腔医学院口腔颌面外科湖北武汉430079

目的:通过大鼠淋巴管畸形(lymphatic malformations,LM)动物模型,探讨抗PD-L1(programmed death ligand 1)治疗在淋巴管畸形中的作用。方法:选择20只雌性成年Wistar大鼠,体重(250±30)g,在颈部皮下注射弗氏不全佐剂(Freund's incomplete adjuvant,FIA)构建大鼠LM动物模型。然后分成4组:PBS组、抗PD-L1组、LPS组、LPS+抗PD-L1组。记录大鼠体重及病变变化,收获病变组织及重要内脏器官进行检测。并通过免疫组织化学法在人LM组织中检测PD-L1表达情况。结果:PD-L1在大鼠LM模型中有表达,在LPS作用下表达进一步升高;抗PD-L1治疗通过抑制淋巴管内皮细胞增殖和成管不仅对非炎症状态LM有治疗效果,对炎症状态下LM也有显著疗效。与正常皮肤对比,PD-L1在人LM病变中也有表达。结论:PD-L1可能与LM的病理过程密切相关,抗PD-L1治疗为LM的治疗提供新的思路。

关键词： Programmed death-ligand 1 淋巴管畸形大鼠模型

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