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.

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.

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.

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.

Unresectable hepatocellular carcinoma:Transarterial chemoembolization combined with lenvatinib in combination with programmed death-1 inhibition is a possible approach

In this editorial,we review the article“Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma”.We specifically focused on whether transarterial chemoembolization combined with lenvatinib in combination with a programmed death 1 inhibitor could be used in patients with unresectable hepatocellular carcinoma.Since both transarterial chemoembolization as well as lenvatinib in combination with programmed death 1 inhibitors play an important role in the treatment of advanced liver cancer,but the combination of all three therapeutic approaches needs more research.

Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.

Drug-eluting beads chemoembolization combined with programmed cell death 1 inhibitor and lenvatinib for large hepatocellular carcinoma

BACKGROUND The combination of transarterial chemoembolization(TACE),lenvatinib,and programmed cell death 1(PD-1)inhibitor has been widely used in the treatment of advanced hepatocellular carcinoma(HCC)and has achieved promising results.However,there are few studies comparing whether drug-eluting beads TACE(DTACE)can bring more survival benefits to patients with large HCC compared to conventional TACE(C-TACE)in this triplet therapy.AIM To compare the efficacy and adverse events(AEs)of triple therapy comprising DTACE,PD-1 inhibitors,and lenvatinib(D-TACE-P-L)and C-TACE,PD-1 inhibitors,and lenvatinib(C-TACE-P-L)in patients with large HCC(maximum diameter≥5 cm),and analyze the prognostic factors.METHODS Following a comprehensive review of our hospital’s medical records,this retrospective study included 104 patients:50 received D-TACE-P-L,and 54 received CTACE-P-L.We employed Kaplan-Meier estimation to assess the median progression-free survival(PFS)between the two groups,utilized Cox multivariate regression analysis to identify prognostic factors,and applied theχ2 test to evaluate AEs.RESULTS The objective response rate(ORR)and median PFS were significantly higher in the D-TACE-P-L group compared to the C-TACE-P-L group(ORR:66.0%vs 44.4%,P=0.027;median PFS:6.8 months vs 5.0 months,P=0.041).Cox regression analysis identified treatment option,portal vein tumor thrombus,and hepatic vein invasion as protective factors for PFS.AEs were comparable between the two CONCLUSION D-TACE-P-L may have significantly better PFS and ORR for large HCC,while exhibiting similar AEs to C-TACE-PL.

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.

Advances on biological evaluation methods of programmed cell death protein-1/ligand-1 inhibitors

Immuno-oncology represents a groundbreaking and well-established field within cancer treatment.Among the various immuno-oncology targets,the exploration of programmed cell death-1/ligand-1 for drug discovery has proven to be one of the most successful endeavors.Remarkably,it took nearly 30 years from the initial target identification to the clinical approval of monoclonal antibodies.Providing suitable and reliable bioassays for drug candidate evaluation is of paramount importance throughout the early stages of drug discovery,from lead compound identification to in vivo efficacy testing.This assay review aims to shed light on diverse assays reported in the literature for testing antagonism activity and efficacy of programmed cell death-1/ligand-1 inhibitors.Each of these assays possesses inherent advantages and can be applied in different research scenarios.The insights presented in this summary can serve as a valuable resource for scientists in this field,aiding in the selection of appropriate assays for their specific investigations.

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.

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.

PD-1抑制剂联合安罗替尼治疗二线化疗失败的老年晚期非小细胞肺癌的效果

目的 探究程序性死亡受体1(PD-1)抑制剂联合安罗替尼治疗二线化疗失败的老年晚期非小细胞肺癌(NSCLC)的临床疗效。方法 选取2019年1月—2021年4月泰州市第二人民医院收治的106例二线化疗失败的老年晚期NSCLC患者作为研究对象,按照随机数字表法分为单药组和联合组,各53例。单药组采用安罗替尼治疗,联合组采用PD-1抑制剂联合安罗替尼治疗。比较两组的疾病控制率、毒副反应发生情况、生存率、肿瘤标志物[细胞角蛋白19片段抗原21-1(CYFRA21-1)、癌胚抗原(CEA)、糖类抗原125(CA125)]、血管新生指标[血管内皮生长因子(VEGF)-A、VEGF受体2(VEGFR2)]、血清驱动蛋白超家族蛋白(KIF)C1、N-钙黏蛋白、生活质量核心量表(QLQ-C30)评分。结果 联合组疾病控制率高于单药组(P<0.05);治疗2个周期后,联合组血清CYFRA21-1、CA125、CEA、VEGF-A、VEGFR2、KIFC1及N-钙黏蛋白水平均低于单药组(P<0.05),QLQ-C30评分低于单药组(P<0.05);两组各毒副反应总发生率比较,差异均无统计学意义(P>0.05);Kaplan-Meier生存分析显示,联合组累积生存率高于单药组(P<0.05)。结论 PD-1抑制剂联合安罗替尼治疗二线化疗失败的老年晚期NSCLC效果显著,可有效调节血清KIFC1、N-钙黏蛋白表达,抑制VEGF-A、VEGFR2水平,降低肿瘤标志物水平,提高生活质量,延长生存时间,安全性高。

PD-1单抗后线辅助治疗晚期结直肠癌患者对胃肠功能、肿瘤标志物的影响

目的分析程序性死亡受体-1(PD-1)单抗后线辅助治疗晚期结直肠癌患者对胃肠功能、肿瘤标志物的影响。方法前瞻性选取2020年1月至2023年1月海口市人民医院收治的105例晚期结直肠癌患者为研究对象,按照随机数字表法将患者分为对照组(n=50)、研究组(n=55)。对照组采用阿帕替尼治疗,研究组在对照组的基础上联合PD-1单抗后线治疗,3周为1个疗程,共治疗4个疗程。比较两组的临床疗效、胃肠功能改善时间,治疗前、治疗12周后的肿瘤标志物[癌胚抗原、糖类抗原(CA)72-4、CA199]、免疫功能(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))指标以及不良反应发生情况。结果治疗12周后,研究组的客观缓解率(ORR)、病情控制率(DCR)分别为78.33%、90.91%,均高于对照组(58.00%、70.00%),差异均有统计学意义(P<0.05)。研究组患者的首次排便时间、首次排气时间、肠鸣音消退时间分别为(51.50±5.02)、(35.52±4.25)、(44.28±4.80)d,均短于对照组[(69.37±6.40)、(50.63±5.10)、(53.50±6.15)d],差异均有统计学意义(P<0.05)。治疗12周后,研究组癌胚抗原、CA72-4、CA199水平分别为(12.57±1.64)ng/mL、(17.60±3.45)U/mL、(58.29±8.70)kU/L,均低于对照组[(17.24±2.50)ng/mL、(27.59±4.67)U/mL、(82.65±12.29)kU/L],差异均有统计学意义(P<0.05)。治疗12周后,研究组CD4^(+)、CD4^(+)/CD8^(+)水平分别为(21.42±3.54)%、0.73±0.30,均低于对照组[(28.39±4.38)%、1.12±0.41],CD8^(+)水平为(30.36±4.52)%,高于对照组[(25.71±3.30)%],差异均有统计学意义(P<0.05)。研究组的不良反应发生率为9.09%,稍低于对照组(16.00%),但两组比较差异无统计学意义(P>0.05)。结论通过PD-1单抗后线辅助治疗可有效改善晚期结直肠癌患者的临床疗效,效果明显,改善胃肠功能,降低肿瘤标志物指标水平,调节机体免疫功能,可为临床干预此病提供参考。

血清细胞因子表达水平与非小细胞肺癌PD-1抑制剂疗效研究进展

程序性死亡受体-1(PD-1)/程序性死亡分子配体-1信号通路抑制剂激活机体免系统后产生的细胞因子在抗肿瘤细胞过程中发挥关键作用。本文回顾近年来接受PD-1抑制剂治疗的非小细胞肺癌患者血清细胞因子表达水平与临床获益的相关性研究,揭示非小细胞肺癌患者PD-1治疗前后白介素-6、白介素-8、肿瘤坏死因子、干扰素、白介素-17A等细胞因子水平变化,为寻找经济、便捷的PD-1抑制剂疗效生物标志物提供思路和线索。

M1型肿瘤相关巨噬细胞在肝细胞癌组织中浸润的意义

背景与目的:肿瘤相关巨噬细胞(tumor-associated macrophages,TAM)是肿瘤微环境中的主要基质细胞,在肿瘤进展过程中发挥重要作用,本研究旨在探究肝细胞癌(hepatocellular carcinoma,HCC)中M1型TAM浸润的临床意义。方法:收集2012年1月—2020年12月在南通大学附属南通第三医院接受手术的HCC患者石蜡包埋组织样本320例,采用免疫组织化学法检测CD86标记的M1型TAM在HCC组织中分布情况,计算阳性细胞密度,根据细胞密度分组:大于平均密度(29个/mm^(2))判定为高密度组,小于或等于平均密度为低密度组;统计分析M1型TAM密度与HCC临床病理学特征、肿瘤浸润CD8^(+)T淋巴细胞之间的相关性及预后意义;采用免疫组织化学法检测程序性死亡配体-1(programmed death ligand-1,PD-L1)的表达情况,根据CD86、PD-L1细胞密度将病例分4组:CD86^(+)高密度组中PD-L1高密度(CD86^(high)PD-L1^(high))和PD-L1低密度(CD86^(high)PD-L1^(low))组;CD86^(+)低密度组中PD-L1高密度(CD86^(low)PD-L1^(high))和PD-L1低密度(CD86^(low)PDL1^(low))组,分析CD86^(+)M1型TAM密度联合PD-L1表达的预后意义。本研究通过南通大学附属南通第三医院伦理委员会批准(伦理编号:EK2022005)。结果:CD86^(+)M1型TAM主要分布于肿瘤间质中;其高密度率为44.7%(143/320)。CD86^(+)M1型TAM密度与CD8^(+)肿瘤浸润细胞毒性T淋巴细胞密度呈正相关(P<0.001)、与乙型肝炎病毒表面抗原(hepatitis B virus surface antigen,HBsAg)阳性呈负相关(P=0.003),与患者性别、年龄、肝硬化、肿瘤大小、组织学分级、微血管侵犯等临床病理学指标均无明显相关性;CD86^(+)M1型TAM高密度组患者总生存期(overall survival,OS)、无病生存期(disease-free survival,DFS)优于低密度组,差异均有统计学意义(P均<0.001)。多因素Cox比例风险回归模型分析显示,低密度CD86^(+)M1型TAM是评估OS和DFS的独立风险因子(OS:HR=1.468,P=0.022;DFS:HR=2.233,P<0.001)。CD86^(high)PD-L1^(high)组HCC患者OS、DFS差于CD86^(high)PD-L1^(low)组,两者差异有统计学意义(P均<0.05)。CD86^(low)PD-L1^(high)组OS、DFS差于CD86^(low)PD-L1^(low)组,两者OS差异有统计学意义(P<0.05),DFS差异无统计学意义。结论:HCC组织中存在高密度CD86^(+)M1型TAM提示患者预后良好,并且是独立的预后因子。HCC组织表达PD-L1提示肿瘤侵袭性增强,患者预后差。

口蹄疫病毒感染后猪PD-1及其配体转录水平变化和免疫抑制机制分析

研究猪感染口蹄疫病毒(Foot-and-mouth disease virus,FMDV)后程序性死亡受体-1(Programmed death-1,PD-1)及其配体(PD-L1、PD-L2),细胞因子[IL-2(Interleukin-2)、IL-10(Interleukin-10)、IFN-γ(Interferon-γ)]mRNA转录水平和外周血单个核细胞(Peripheral blood mononuclear cells,PBMCs)增殖能力,探讨PD-1/PD-Ls通路在FMDV引起免疫抑制过程中的作用机制。结果表明,猪感染FMDV后3、7、14、17 d,PD-1的mRNA转录水平显著或极显著升高,感染后7 d达到峰值,之后逐渐降低;感染FMDV后3 d和7 d,PD-L1的mRNA转录水平极显著升高;感染FMDV后3 d,PD-L2的mRNA转录水平显著升高。感染FMDV后3、7 d,IL-2的mRNA转录水平显著下降;感染FMDV后1、3 d,IFN-γ的mRNA转录水平极显著下降,IL-2和IFN-γ的mRNA转录水平与PD-1及其配体mRNA转录水平变化趋势相反;感染FMDV后3、7、14 d,IL-10的mRNA转录水平显著或极显著升高,与PD-1及其配体mRNA转录水平变化趋势相同。感染FMDV后,全血中FMDV的病毒载量随着感染后时间的推进逐渐升高,感染后7 d达到峰值,与PD-1及其配体mRNA转录水平变化趋势总体上相同。感染后7 d,PBMCs的增殖能力明显降低。综上,FMDV感染猪后,总体上上调了PD-1及其配体的mRNA转录水平,是FMDV感染引起机体免疫抑制的重要致病机制。