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

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 characteristics.METHODS We retrospectively reviewed 284 GC patients who underwent D2-gastrectomy.PD-L1 was evaluated by immunohistochemistry(clone SP142)using the com-bined positive score.All PD-L1+PT staged as pN+were also tested for PD-L1 expression in their LNM.PD-L1(-)GC with pN+served as the comparison group.RESULTS 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 LNM.Regarding PD-L1(-)PT,9.1%(4/44)had PD-L1+in the LNM.The agreement between PT and LNM had a kappa value of 0.483.Larger tumor size and moderate/severe peritumoral inflammatory response were associated with PD-L1 positivity in both sites.There 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 LNM.This disagreement in PD-L1 status may emphasize the importance of considering different tumor sites for analyses to select patients for immunotherapy.

Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer according to programmed cell death ligand 1

BACKGROUND Bevacizumab,an anti-vascular endothelial growth factor(VEGF)monoclonal antibody,inhibits angiogenesis and reduces tumor growth.Serum VEGF-C,lactate dehydrogenase,and inflammatory markers have been reported as predictive markers related to bevacizumab treatment.Programmed cell death ligand 1(PD-L1)could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis.AIM To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer(CRC)according to the expression of PD-L1.METHODS This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24,2014 and February 28,2022,at Samsung Medical Center(Seoul,South Korea).Analysis of patient data included evaluation of PD-L1 expression by the combined positive score(CPS).We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC.RESULTS A total of 124 patients was included in this analysis.Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy.While 77%of patients received FOLFOX,23%received FOLFIRI as backbone first-line chemotherapy.The numbers of patients with a PD-L1 CPS of 1 or more,5 or more,or 10 or more were 105(85%),64(52%),and 32(26%),respectively.The results showed no significant difference in progression-free survival(PFS)and overall survival(OS)with bevacizumab treatment between patients with PDL1 CPS less than 1 and those with PD-L1 CPS of 1 or more(PD-L1<1%vs PD-L1≥1%;PFS:P=0.93,OS:P=0.33),between patients with PD-L1 CPS less than 5 and of 5 or more(PD-L1<5%vs PD-L1≥5%;PFS:P=0.409,OS:P=0.746),and between patients with PD-L1 CPS less than 10 and of 10 or more(PD-L1<10%vs PD-L1≥10%;PFS:P=0.529,OS:P=0.568).CONCLUSION Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.

Cytokine release syndrome triggered by programmed death 1 blockade(sintilimab)therapy in a psoriasis patient:A case report

BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor+chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1(PD-1)inhibitor and che-motherapy is approved as a standard first-or second-line treatment in patients with advanced oesophageal or gastric cancer.However,it is unclear whether this combination is superior to chemotherapy alone.AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer,gastroesophageal junction(GEJ)cancer,or oesophageal carcinoma.METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer.We employed either random or fixed models to analyze the outcomes of each clinical trial,en-compassing data on overall survival(OS),progression-free survival(PFS),objective response rate,and adverse events(AEs).RESULTS Nine phase 3 clinical trials(7016 advanced oesophageal and gastric cancer patients)met the inclusion criteria.Our meta-analysis demonstrated that the pooled PD-1 inhibitor+chemotherapy group had a significantly longer OS than the chemotherapy-alone group[hazard ratio(HR)=0.76,95%confidence interval(CI):0.71-0.81];the pooled PFS result was consistent with that of OS(HR=0.67,95%CI:0.61-0.74).The count of patients achieving an objective response in the PD-1 inhibitor+chemotherapy group surpassed that of the chemotherapy-alone group[odds ratio(OR)=1.86,95%CI:1.59-2.18].AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group,regardless of whether≥grade 3 only(OR=1.30,95%CI:1.07-1.57)or all AE grades(OR=1.88,95%CI:1.39-2.54)were examined.We performed a subgroup analysis based on the programmed death-ligand 1(PD-L1)combined positive score(CPS)and noted extended OS and PFS durations within the CPS≥1,CPS≥5,and CPS≥10 subgroups of the PD-1 inhibitor+chemotherapy group.CONCLUSION In contrast to chemotherapy alone,the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer,GEJ tumor,or oesophageal cancer.This holds true particularly for individuals with PD-L1 CPS scores of≥5 and≥10.

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma,a malignancy that arises in the cells of the pancreas,is a devastating disease with unclear etiology and often poor prognosis.Locally advanced pancreatic cancer,a stage where the tumor has grown significantly but has not yet spread to distant organs,presents unique challenges in treatment.This article aims to discuss the current strategies,challenges,and future directions in the management of locally advanced pancreatic adenocarcinoma(LAPC).AIM To investigate the feasibility and efficacy of programmed cell death 1(PD-1)inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC.METHODS Eligible patients had LAPC,an Eastern cooperative oncology group performance status of 0 or 1,adequate organ and marrow functions,and no prior anticancer therapy.In the observation group,participants received intravenous sintilimab 200 mg once every 3 wk,and received concurrent chemoradiotherapy(concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-140 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression,death,or unacceptable toxicity).In the control group,participants only received concurrent chemoradiotherapy.From April 2020 to November 2021,64 participants were finally enrolled with 34 in the observation group and 30 in the control group.RESULTS Thirty-four patients completed the scheduled course of chemoradiotherapy,while 32(94.1%)received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group.Thirty patients completed the scheduled course of chemoradiotherapy in the control group.Based on the Response Evaluation Criteria in Solid Tumors guidelines,the analysis of the observation group revealed that a partial response was observed in 11 patients(32.4%),stable disease was evident in 19 patients(55.9%),and 4 patients(11.8%)experienced progressive disease;a partial response was observed in 6(20.0%)patients,stable disease in 18(60%),and progressive disease in 6(20%)in the control group.The major toxic effects were leukopenia and nausea.The incidence of severe adverse events(AEs)(grade 3 or 4)was 26.5%(9/34)in the observation group and 23.3%(7/30)in the control group.There were no treatment-related deaths.The observation group demonstrated a significantly longer median overall survival(22.1 mo compared to 15.8 mo)(P<0.05)and progression-free survival(12.2 mo vs 10.1 mo)(P<0.05)in comparison to the control group.The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group(P>0.05).CONCLUSION Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients,and warrants further investigation.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.

Expression characteristics of peripheral lymphocyte programmed death 1 and FoxP3+ Tregs in gastric cancer during surgery and chemotherapy

BACKGROUND Programmed death 1(PD-1)and CD4^(+)CD25^(+)FoxP3^(+)expression in peripheral blood T-cells has been previously reported in various types of cancer.However,the specific variation tendency during surgery and chemotherapy,as well as their relationship in gastric cancer patients,still remain unclear.Understanding this aspect may provide some novel insights for future studies on tumor recurrence and tumor immune escape,and also serve as a reference for determining the optimal timing and dose of clinical anti-PD-1 antibodies.AIM To observe and analyze the expression characteristics of peripheral lymphocyte PD-1 and FoxP3^(+)regulatory T cells(FoxP3^(+)Tregs)before and after surgery or chemotherapy in gastric cancer patients.METHODS Twenty-nine stomach cancer patients undergoing chemotherapy after a D2 gastrectomy provided 10 mL peripheral blood samples at each phase of the perioperative period and during chemotherapy.This study also included 29 agematched healthy donors as a control group.PD-1 expression was detected on lymphocytes,including CD4^(+)CD8^(+)CD45RO^(+),CD4^(+)CD45RO^(+),and CD8^(+)CD45RO^(+)lymphocytes as well as regulatory T cells.RESULTS We observed a significant increase of PD-1 expression on immune subsets and a larger number of FoxP3^(+)Tregs in gastric cancer patients(P<0.05).Following D2 gastrectomy,peripheral lymphocytes PD-1 expression and the number of FoxP3^(+)Tregs notably decrease(P<0.05).However,during postoperative chemotherapy,we only observed a decrease in PD-1 expression on lymphocytes in the CD8^(+)CD45RO^(+)and CD8^(+)CD45RO^(+)populations.Additionally,linear correlation analysis indicated a positive correlation between PD-1 expression and the number of CD4^(+)CD45RO^(+)FoxP3high activated Tregs(aTregs)on the total peripheral lymphocytes(r=0.5622,P<0.0001).CONCLUSION The observed alterations in PD-1 expression and the activation of regulatory T cells during gastric cancer treatment may offer novel insights for future investigations into tumor immune evasion and the clinical application of anti-PD-1 antibodies in gastric cancer.

Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy

Lymphoma,which is highly malignant,stems from lymph nodes and lymphoid tissue.Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2),which binds with programmed cell death 1 protein(PD-1)to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance.Recently,immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab)have been introduced into the lymphoma treatment algorithm and have shown remarkable clinical efficacy and greatly improve prognosis in lymphoma patients.Accordingly,the number of lymphoma patients who are seeking treatment with PD-1 inhibitors is growing annually,which results in an increasing number of patients developing immune-related adverse events(irAEs).The occurrence of irAEs inevitably affects the benefits provided by immunotherapy,particularly when PD-1 inhibitors are applied.However,the mechanisms and characteristics of irAEs induced by PD-1 inhibitors in lymphoma need further investigation.This review article summarizes the latest research advances in irAEs during treatment of lymphoma with PD-1 inhibitors.A comprehensive understanding of irAEs incurred in immunotherapy can help to achieve better efficacy with PD-1 inhibitors in lymphoma.

Programmed death ligand-1 expression and its prognostic role in esophageal squamous cell carcinoma

AIM To investigate the expression and prognostic role of programmed death ligand-1(PD-L1) in locally advanced esophageal squamous cell carcinoma(ESCC).METHODS A total of 200 patients with ESCC who underwent radical esophagectomy with standard lymphadenectomy as the initial definitive treatment in Seoul National University Hospital from December 2000 to April 2013 were eligible for this analysis. Tissue microarrays were constructed by collecting tissue cores from surgical specimens, and immunostained with antibodies directed against PD-L1, p16, and c-Met. Medical records were reviewed retrospectively to assess clinical outcomes. Patients were divided into two groups by PD-L1 status, and significant differences in clinicopathologic characteristics between the two groups were assessed. RESULTS Tumor tissues from 67 ESCC patients(33.5%) were PDL1-positive. Positive p16 expression was observed in 21 specimens(10.5%). The H-score for c-Met expression was ≥ 50 in 42 specimens(21.0%). Although PDL1-positivity was not significantly correlated with any clinical characteristics including age, sex, smoking/alcoholic history, stage, or differentiation, H-scores for c-Met expression were significantly associated with PDL1-positivity(OR = 2.34, 95%CI: 1.16-4.72, P = 0.017). PD-L1 expression was not significantly associated with a change in overall survival(P = 0.656). In contrast, the locoregional relapse rate tended to increase(P = 0.134), and the distant metastasis rate was significantly increased(HR = 1.72, 95%CI: 1.01-2.79, P = 0.028) in patients with PD-L1-positive ESCC compared to those with PD-L1-negative ESCC.CONCLUSION PD-L1 expression is positively correlated with c-Met expression in ESCC. PD-L1 may play a critical role in distant failure and progression of ESCC.

Significance of 125I radioactive seed implantation on growth differentiation factor and programmed death receptor-1 during treatment of oral cancer

BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.

Myricetin inhibits interferon-γ-induced programmed death ligand-1 and indoleamine 2,3-dioxygenase 1 expression in lung cancer cells

OBJECTIVE Programmed death ligand-1(PD-L1)and indoleamine 2,3-dioxygenase 1(IDO1)are immune checkpoints which can be induced by interferon-γ(IFN-γ)in the tumor microenvironment,leading to immune escape of tumors.Myricetin(MY)is a flavonoid distributed in many edible and medicinal plants.The aim of this study is to clarify the effect and the mechanism of MY on inhibiting IFN-γ-induced PD-L1 and IDO1 in lung cancer cells.METHODS Expressions of PD-L1 and major histocompatibility complex-I(MHC-I)were evaluated by flow cytometry and Western blotting,and the expression of IDO1 was measured by Western blotting.qRT-PCR was used to detect their mRNA levels.The function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line that overexpressing PD-1.Molecular docking analysis,Western blotting and immunofluorescence were used for mechanism study.RESULTS MY potently inhibited IFN-γ-induced PD-L1 and IDO1 expression in human lung cancer cells,while didn't show obvious effect on the expression of MHC-I.In addition,MY restored the survival,proliferation,CD69 expression and interleukin-2(IL-2)secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells in the co-culture system.Mechanistically,IFN-γup-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis,which was targeted and inhibited by MY.CONCLUSION Our research revealed a new insight into the anti-tumor effects of MY which inhibited IFN-γ-induced PD-L1 and IDO1 expression,supporting the potential of MY in anti-tumor immunotherapy.

Natural course of chronic hepatitis B is characterized by changing patterns of programmed death type-1 of CD8-positive T cells

AIM:To investigate if and how programmed death type-1(PD-1)expression affects the natural course of hepatitis B virus(HBV)infection. METHODS:Sixty-four patients in different natural stages of chronic HBV infection were enrolled in this study.PD-1 expression in total T cells was detected by flow cytometry.Levels of total CD8+T cell responses and proliferation in relation to PD-1 expression levels were analyzed with intracellular staining and PD-1/ PD-L1 blockage. RESULTS:The PD-1 expression in T cells was dynamically changed during the natural course of chronic HBV infection,did not significantly increase in the immune tolerance phase,and returned to normal in the inactive virus carrier stage.Blockage of the PD-1/PD-L1 pathway could not affect the T-cell response in the immune tolerance and inactive virus carrier stages of chronic HBV infection.However,it could significantly restore the T-cell response in the immune clearance stage of chronic HBV infection.Furthermore,the PD-1 expression level in T cells was associated with the alanine aminotransferase level during the immune clearance stage of chronic HBV infection. CONCLUSION:The PD-l/PD-L1 pathway plays a different role in T-cell response during the natural course of chronic HBV infection.

Advances in immuno-oncology biomarkers for gastroesophageal cancer:programmed death ligand 1,microsatellite instability,and beyond

Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.

Programmed cell death, antioxidant response and oxidative stress in wheat f lag leaves induced by chemical hybridization agent SQ-1

Male sterility induced by a chemical hybridization agent （CHA） is an important tool for utilizing crop heterosis. Leaves, especially the flag leaves, as CHA initial recipients play a decisive role in inducing male sterility. To investigate effects of different treatment times of CHA-SQ-1 used, morphological, biochemical and physiological responses of wheat flag leaves were detected in thistudy. CHA induced programmed cell death （PCD） as shown in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling （TUNEL） and DNA laddering analysis. In the early phase, CHA-SQ-1 trig- gered organelle changes arid PCD in wheat leaves accompanied by excess production of reactive oxygen species （O2- and H202） and down-regulation of the activities of superoxide dismutase （SOD）, catalase （CAT） and guaiacol peroxidase （POD）. Meanwhile, leaf cell DNAs showed ladder-like patterns on agarose gel, indicating that CHA-SQ-1 led to the activation of the responsible endonuclease. The oxidative stress assays showed that lipid peroxidation was strongly activated and photosynthesis was obviously inhibited in SQ-l-induced leaves. However, CHA contents in wheat leaves gradually reduced along with the time CHA-SQ-1 applied. Young flags returned to an oxidative/antioxidative balance and ultimately developed into mature green leaves. These results provide explanation of the relations between PCD and anther abortion and practical application of CHA for hybrid breeding.

Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors

The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1(PD-1)and anti-programmed cell death protein ligand 1(PD-L1) monoclonal antibodies, has opened new scenarios in the management of non-small cell lung cancer(NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry(IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered(tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC.

Programmed death 1 and programmed death ligand 1 expressions in patients with chronic hepatitis B

BACKGROUND: The role of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) in persistent HBV infection is controversial. Increasing PD-1 and PD-L1 expression has been found in hepatitis B patients during immune clearance phase, but not in HBV-tolerant patients. We investigated PD-1 and PD-L1 expression and inflammation in chronic hepatitis B. METHODS: Twenty patients with chronic hepatitis B participated in this study. Fifteen patients were in the immune clearance phase, and 5 were in the immune inactive phase. Circulating HBV-specific T cells were analyzed by flow cytometric detection of major histocompatibility complex (MHC) class I peptide complexes, known as pentamers. Intra-hepatic PD-1 and PD-L1 expressions were analyzed by immunostaining. RESULTS: The frequency of pentamers, including core 18-27 (1.88%±0.36%), env 335-343 (1.85%±0.37%), and pol 575-583 (1.56%±0.29%) was 8.30-, 7.71- and 8.48-fold greater during immune clearance phase than those during the immune inactive phase. In addition, more than 70% of circulating pentamers were PD-1 positive. During immune clearance phase, the numbers of intra-hepatic PD-1 and PD-L1 positive cells were 108±23/HPF and 97±20/HPF respectively, in contrast, there was a paucity of PD-1 and PD-L1 positive cells in the immune inactive phase. The numbers of intra-hepatic PD-1 and PD-L1 positive cells were positively correlated with serum alanine aminotransferase and the number of intra-hepatic CD8 + T cells. Immunofluorescence showed that almost all of the intra- hepatic CD8 + T cells were PD-1 and CCR6 positive. These cells aggregated around macrophage inflammatory protein-3 alpha (MIP3α) positive cells and mixed with PD-L1 positive cells.CONCLUSIONS: PD-1 and PD-L1 expressions were significantly correlated with inflammation. CCR6 and PD-1 co-expressed in the same cells; these cells were increased both in circulation and the inflamed liver and aggregated around MIP3α positive cells. The mixture of CCR6 and PD-1, MIP3α and PD-L1 positive cells created immune response compartments which played an important role in specific immune response in HBV immune clearance.

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

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 poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stageT1-4 N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

Comprehensive insights into the effects and regulatory mechanisms of immune cells expressing programmed death-1/programmed death ligand 1 in solid tumors

The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.

Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas

BACKGROUND Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1(PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas(G-NECs) remains unknown.AIM To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.METHODS We investigated the expression of PD-L1 on tumor cells and PD-1^+, CD8^+, and FOXP3^+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR.RESULTS Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43G-NECs, 21(48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival(OS). The high expression of PD-L1 was correlated with abundant PD-1^+ tumor infiltrating lymphocytes(TILs) instead of CD8^+ TILs and FOXP3^+ regulatory T cells(Tregs).Our analysis also suggested that the infiltration of CD8^+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance(P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without.CONCLUSION Our data demonstrated for the first time that high expression of PD-L1 in GNECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in GNECs.