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World Journal of Stem Cells 2021年第7期13卷 795-824页

作者： Caecilia H C Sukowati Korri Elvanita El-Khobar Claudio Tiribelli Centro Studi Fegato Fondazione Italiana Fegato ONLUSTrieste 34149Italy Hepatitis Unit Eijkman Institute for Molecular BiologyJakarta 10430Indonesia

Hepatocellular carcinoma(HCC)is a heterogeneous malignancy related to diverse etiological *** oncogenic mechanisms and genetic variations lead to multiple HCC molecular ***,an immune-based strategy using immune checkpoint inhibitors(ICIs)was presented in HCC therapy,especially with ICIs against the programmed death-1(PD-1)and its ligand ***,despite the success of anti-PD-1/PD-L1 in other cancers,a substantial proportion of HCC patients fail to *** this review,we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells(CSCs).Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to ***-L1 expression in tumoral tissues is differentially expressed in CSCs,particularly in those with a close association with the tumor *** information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.

关键词： Hepatocellular carcinoma programmed death-1 programmed death ligand 1 Cancer stem cells Cancer heterogeneity Genetic variants

Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer

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World Journal of Gastrointestinal Oncology 2020年第11期12卷 1216-1236页

作者： Yi-Zhi Liu Da-Ting Han Dan-Rong Shi Bo Hong Yun Qian Zhi-Gang Wu Shu-Hao Yao Tao-Ming Tang Ming-Hai Wang Xiang-Ming Xu Hang-Ping Yao Department of Cancer Biology Research State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Pathology The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Clinical Laboratory The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Stomatology Wenzhou Medical University Renji CollegeWenzhou 325035Zhejiang ProvinceChina Cancer Biology Research Center and Department of Pharmaceutical Sciences School of PharmacyTexas Tech University Health Sciences CenterAmarilloTX 79106United States Department of Cancer Biology Research The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

BACKGROUND programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating tumor *** To identify the patterns of RON and PD-L1 expression and explore their clinical significance in *** Gene expression data from the Gene Expression Omnibus database(GEO;n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine(FAHZUSM;n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western *** In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121(32%), 43(11%), 91(24%), and 51(13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment(P 1). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC *** RON, PD-L1, and their crosstalk

关键词： Colorectal cancer programmed death ligand 1 Prognosis Recepteur d'origine nantais Tumor infiltrating mononuclear cells Tumor microenvironment

Intermittent hypoxia enhances the tumor programmed death ligand 1 expression in mice

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Intermittent hypoxia enhances the tumor programmed death lig...

programmed death 1, ligand 1 and 2 correlated genes and their association with mutation, immune infiltration and clinical outcomes of hepatocellular carcinoma

中国睡眠研究会第十届全国学术年会

作者： Xiao-Bin Zhang Liu-Xia Li Yi-Ming Zeng Chih-Yuan Ko Yan-Ping Du Miao Wang Hui-Qing Zeng Xiongbiao Luo Department of Respiratory Medicine Zhongshan HospitalXiamen University Department of Respiratory and Critical Care Medicine the Second Affiliated Hospital of Fujian Medical Universitythe Second Clinical Medical College of Fujian Medical UniversityCenter of Respiratory Medicine of Fujian Province Computer College Xiamen University

Objective: As a pathophysiological hallmark of obstructive sleep apnea（OSA）,intermittent hypoxia（IH） promotes the tumor *** high expression of programmed death 1 and programmed death ligand 1（PDL-1） in tumor leads to immune evasion,subsequently aggravates tumor *** study aims to determine the tumor PDL-1 expression under IH *** and methods: A total of 24 male C57 BL/6 J mice were randomly assigned to the normoxia（control,CTL） group and the IH *** in IH group were subjected to IH condition for 5 *** Lewis lung cells were injected into the flank of each mice after 1 weeks of IH *** weight,tumor volume,and tumor weight were *** blotting was conducted to assess the hypoxia inducible factor 1?（HIF-1 ?） and PDL-1 in tumor tissue between the two *** PDL-1 expression were also detected by immunohistochemistry（IHC）.Results: Mice in IH group had low body weight,high tumor volume and tumor *** blotting results showed higher tumor HIF-1? and PDL-1 expression levels in mice under the IH condition than under the CTL *** IHC results also confirmed that compared to the CTL group,mice in the IH group had high PDL-1 ***: IH can enhance the tumor PDL-1 expression,we speculate that high PDL-1 levels is associated with poor outcome in patients with OSA and *** results of the present provided experiment evidence for using anti-PD-1/PDL-1 antibodies to treat cancer among OSA patients.

关键词： intermittent hypoxia programmed death ligand 1 tumor sleep apnea

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World Journal of Gastrointestinal Oncology 2020年第11期12卷 1255-1271页

作者： Qiu-Ju Sheng Wen-Yue Tian Xiao-Guang Dou Chong Zhang Yan-Wei Li Chao Han Yao-Xin Fan Ping-Ping Lai Yang Ding Department of Infectious Diseases Shengjing Hospital of China Medical UniversityShenyang 110022Liaoning ProvinceChina

BACKGROUND The exact regulation network of programmed death 1(PD-1), programmed death ligand 1(PD-L1), and programmed death ligand 2(PD-L2) signaling in immune escape is largely unknown. We aimed to describe the gene expression profiles related to PD-1 as well as its ligands PD-L1 and PD-L2, thus deciphering their possible biological processes in hepatocellular carcinoma(HCC).AIM To find the possible mechanism of function of PD-1, PD-L1, and PD-L2 in *** Based on the expression data of HCC from The Cancer Genome Atlas, the PD-1/PD-L1/PD-L2 related genes were screened by weighted correlation network analysis method and the biological processes of certain genes were enriched. Relation of PD1/PD-L1/PD-L2 with immune infiltration and checkpoints was investigated by co-expression analysis. The roles of PD-1/PD-L1/PD-L2 in determination of clinical outcome were also *** Mutations of calcium voltage-gated channel subunit alpha1 E, catenin beta 1, ryanodine receptor 2, tumor suppressor protein p53, and Titin altered PD-1/PDL1/PD-L2 expression profiles in HCC. PD-1, PD-L1, and PD-L2 related genes were mainly enriched in biological procedures of T cell activation, cell adhesion, and other important lymphocyte effects. In addition, PD-1/PD-L1/PD-L2 was related with immune infiltration of CD8 T cells, cytotoxic lymphocytes,fibroblasts, and myeloid dendritic cells. Immune checkpoints of CTLA4, CD27, CD80, CD86, and CD28 were significantly related to the PD-1/PD-L1/PD-L2 axis. Clinically, PD-1 and PD-L2 expression was correlated with recurrence(P = 0.005 for both), but there was no significant correlation between their expression and HCC patient *** Mutations of key genes influence PD-1, PD-L1, and PD-L2 expression. PD-1, PDL1, and PD-L2 related genes participate in T cell activation, cell adhesion, and other important lymphocyte effects. The finding that PD-1/PD-L1/PD-L2 is related to immune infiltration and other immune checkpoints would exp

关键词： programmed death 1 programmed death ligand 1 programmed death ligand 2 Immune Hepatocellular carcinoma Cancer

Assessment of programmed death-ligand 1 expression in primary tumors and paired lymph node metastases of gastric adenocarcinoma

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 883-893页

作者： Brendha Cação Coimbra Marina Alessandra Pereira Leonardo Cardili Venancio Avancini Ferreira Alves Evandro Sobroza de Mello Ulysses Ribeiro Jr Marcus Fernando Kodama Pertille Ramos Department of Gastroenterology Instituto do CancerHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloFaculdade de MedicinaUniversidade de São PauloSão Paulo 01246000Brazil Department of Pathology Instituto do CancerHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloSão Paulo 01246000Brazil

BACKGROUND Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1)immuno-therapy has demonstrated promising results on gastric cancer(GC).However,PD-L1 can express differently between metastatic sites and primary tumors(PT).AIM To compare PD-L1 status in PT and matched lymph node metastases(LNM)of GC patients and to determine the correlation between the PD-L1 status and clinicopathological *** We retrospectively reviewed 284 GC patients who underwent ***-L1 was evaluated by immunohistochemistry(clone SP142)using the com-bined positive *** PD-L1+PT staged as pN+were also tested for PD-L1 expression in their ***-L1(-)GC with pN+served as the comparison *** Among 284 GC patients included,45 had PD-L1+PT and 24 of them had pN+.For comparison,44 PD-L1(-)cases with pN+were included(sample loss of 4 cases).Of the PD-L1+PT,54.2%(13/24 cases)were also PD-L1+in the *** PD-L1(-)PT,9.1%(4/44)had PD-L1+in the *** agreement between PT and LNM had a kappa value of *** tumor size and moderate/severe peritumoral inflammatory response were associated with PD-L1 positivity in both *** was no statistical difference in overall survival for PT and LNM according to the PD-L1 status(P=0.166 and P=0.837,respectively).CONCLUSION Intra-patient heterogeneity in PD-L1 expression was observed between the PT and matched *** disagreement in PD-L1 status may emphasize the importance of considering different tumor sites for analyses to select patients for immunotherapy.

关键词： Gastric cancer Lymph node programmed death ligand 1 Stomach neoplasms Immunohistochemistry Metastasis

Nagilactone E increases PD-L1 expression through activation of c-Jun in lung cancer cells

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Chinese Journal of Natural Medicines 2020年第7期18卷 517-525页

作者： CHEN Yu-Chi HUANG Mu-Yang ZHANG Le-Le FENG Zhe-Ling JIANG Xiao-Ming YUAN Luo-Wei HUANG Run-Yue LIU Bo YU Hua WANG Yi-Tao CHEN Xiu-Ping LIN Li-Gen LU Jin-Jian State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China School of Medicine Chengdu UniversityChengdu 610106China The Second Affiliated Hospital of Guangzhou University of Chinese Medicine(Guangdong Provincial Hospital of Chinese Medicine) Guangzhou 510120China

Nagilactone E(NLE),a natural product with anticancer activities,is isolated from Podocarpus *** this study,we reported that NLE increased programmed death ligand 1(PD-L1)expressions at both protein and mRNA levels in human lung cancer cells,and enhanced its localization on the cell ***,NLE increased the phosphorylation and expression of cJun,and promoted the localization of c-Jun in the nucleus,while silencing of c-Jun by small interfering RNA(siRNA)reduced NLEinduced *** study showed that NLE activated the c-Jun N-terminal kinases(JNK),the upstream of c-Jun,and its inhibitor SP600125 reversed the NLE-increased ***,NLE-induced PD-L1 increased the binding intensity of PD-1 on the cell *** summary,NLE upregulates the expression of PD-L1 in lung cancer cells through the activation of JNK-c-Jun axis,which has the potential to combine with the PD-1/PD-L1 antibody therapies in lung cancer.

关键词： programmed death ligand 1 Nagilactone E Lung cancer c-Jun JNK

Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4118-4133页

作者： Mengyi Yan Xiayun Chen Xiaotong Li Qianqian Liu Baixue Yu Yi Cen Wei Zhang Yibin Liu Xinxuan Li Ying Chen Tao Wang Shiying Li The Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory Diseasethe School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Department of Anesthesiology the Second Clinical School of Guangzhou Medical UniversityGuangzhou 511436China State Key Laboratory of Respiratory Diseases Guangdong Key Laboratory of Vascular DiseasesGuangzhou Institute of Respiratory Healththe first Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510120China Department of Pulmonary and Critical Care Medicine Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional *** this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β-catenin signal *** synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of *** the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated *** the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung *** work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

关键词： Transferrin receptor β-Catenin signal pathway Tumor targeting Photodynamic therapy Immunotherapy Immunogenic cell death programmed death ligand 1 C-C motif chemokine ligand 4

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

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World Journal of Gastroenterology 2024年第4期30卷 318-331页

作者： Yu-Zhe Cao Guang-Lei Zheng Tian-Qi Zhang Hong-Yan Shao Jia-Yu Pan Zi-Lin Huang Meng-Xuan Zuo Department of Minimally Invasive Interventional Therapy Sun Yat-sen University Cancer CenterGuangzhou 510060Guangdong ProvinceChina Department of Minimally Invasive Interventional Therapy State Key Laboratory of Oncology in South ChinaGuangzhou 510060Guangdong ProvinceChina Department of Minimally Invasive Interventional Therapy Guangdong Provincial Clinical Research Center for CancerGuangzhou 510060Guangdong ProvinceChina

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating ***,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are *** To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world *** Several electronic databases were searched to identify eligible randomized controlled trials for this ***-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were *** was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April *** score matching(PSM)was performed to balance the bias between the *** Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the *** A total of 13 randomized controlled trials were *** alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the *** triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for *** findings confirm that triple therapy is more effective for uHCC patients than AIPB.

关键词： Unresectable hepatocellular carcinoma Hepatic arterial infusion chemotherapy Angiogenesis inhibitors programmed cell death protein 1 programmed death ligand 1

Efficacy and safety of immune checkpoint inhibitors for advanced non-small cell lung cancer with or without PD-L1 selection:A systematic review and network meta-analysis

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Chinese Medical Journal 2023年第18期136卷 2156-2165页

作者： Yan Li Xueyan Liang Huijuan Li Xiaoyu Chen Department of Pharmacy Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous RegionNanningGuangxi 530021China Phase 1 Clinical Trial Laboratory Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous RegionNanningGuangxi 530021China

Background:Immune checkpoint inhibitors(ICIs)are standard treatments for advanced non-small cell lung cancer(NSCLC);however,evidence regarding their relative efficacy and safety is *** study compared the efficacy and safety of all currently available ICI treatments in patients with advanced NSCLC to identify optimal treatment ***:PubMed,Cochrane Central Register of Controlled Trials(CENTRAL),MEDLINE,and Embase databases were systematically searched for randomized controlled trials(RCTs)published up to August 8,*** primary outcomes were overall survival(OS)and progression-free survival(PFS).Secondary outcomes included objective response rate(ORR)and adverse events(AEs).Results:Forty RCTs involving 22,526 patients were selected,and a total of 26 treatment regimens were *** with anti-programmed cell death protein-1(anti-PD-1)provided superior OS compared with anti-programmed death ligand 1(anti-PD-L1)*** plus platinum-based chemotherapy(PBC)were superior to ICIs treatment alone,although the addition of PBC increased treatment *** ranked first for OS and lowest for any-grade AEs in advanced NSCLC patients without PD-L1 *** grade≥3 AEs,the toxicity of ICI monotherapy or ICI-ICI combination was consistently lower than that of the other *** patients without PD-L1 selection,cemiplimab showed the best OS,pembrolizumab plus docetaxel(Pem-DXT)showed the best PFS,and atezolizumab plus bevacizumab and PBC(Atezo-Beva-PBC)showed the best *** plus PBC and Atezo-Beva-PBC were the most likely optimal treatments for OS and PFS in patients with PD-L1 expression<1%,*** patients with PD-L1 expression≥1%,treatment regimens containing anti-PD-1 provided superior OS benefits compared with those of anti-PD-L1 treatment,and sintilimab plus PBC(Sint-PBC)provided the best OS benefit;as for PFS,ICI plus PBC consistently showed greater PFS benefits than ICI or PBC ***

关键词： Non-small cell lung cancer Immune checkpoint inhibitor programmed death ligand 1 Cemiplimab Bayesian network meta-analysis

PD-1/PD-L1 Signaling Pathway and Tumor Immune Escape

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Journal of Biosciences and Medicines 2023年第3期11卷 9-16页

作者： Zhenqi Xu Wei Du Department of Oncology The First Affiliated Hospital of Yangtze University Jingzhou China

PD-1 and its ligands PD-L1 and PD-L2 are widely expressed on the surface of a variety of cells and are a group of costimulatory molecules related to negative immune regulation. The activation of the PD-1/PD-L1 signaling pathway is beneficial for tumors to escape from immune surveillance, but the specific tumor immune escape mechanism is not yet clear. As far as the efficacy of anti-PD-1 and anti-PD-L1 antibodies is concerned, more in-depth research on tumor immune escape mechanisms is still needed. The article summarizes these findings to provide ideas for antitumor immunotherapy.

关键词： programmed death 1 programmed death ligand 1 Neoplasms Immunotherapy