Soluble programmed death-1 is predictive of hepatitis B surface antigen loss in chronic hepatitis B patients after antiviral treatment

BACKGROUND Hepatitis B surface antigen(HBsAg)loss,a functional cure in patients with chronic hepatitis B(CHB)undergoing antiviral therapy,might be an ideal endpoint of antiviral treatment in clinical practice.The factors that contribute to the functional cure remain unclear,and the predictors of functional cure are worth exploring.The concentration and kinetics of soluble programmed death-1(sPD-1)in patients with CHB may play an important role in elucidating the immune response associated with functional cure after nucleos(t)ide analogs therapy.AIM To investigate the factors associated with HBsAg loss and explore the influence of sPD-1 Levels.METHODS This study analyzed the data and samples from patients with CHB who underwent antiviral treatment in a non-interventional observational study conducted at Peking University First Hospital in Beijing(between 2007 and 2019).All patients were followed up:Serum samples were collected every 3 mo during the first year of antiviral treatment and every 6 mo thereafter.Patients with positive hepatitis B e antigen levels at baseline and with available sequential samples who achieved HBsAg loss during antiviral treatment served as the case group.This case group(n=11)was further matched to 44 positive hepatitis B e anti patients without HBsAg loss as controls.The Spearman’s rank correlation test and receiver operating characteristic curves analysis were performed.RESULTS The sPD-1 Levels were higher in patients with HBsAg loss than in those without HBsAg loss from baseline to month 96,and the differences were significant between the groups at baseline(P=0.0136),months 6(P=0.0003),12(P<0.0001),24(P=0.0007),48(P<0.0001),and 96(P=0.0142).After 6 mo of antiviral treatment,the sPD-1 levels were positively correlated with alanine transaminase(ALT)levels(r=0.5103,P=0.0017),and the sPD-1 levels showed apparent correlation with ALT(r=0.6883,P=0.0192)and HBV DNA(r=0.5601,P=0.0703)levels in patients with HBsAg loss.After 12 mo of antiviral treatment,the sPD-1 levels also showed apparent correlation with ALT(r=0.8134,P=0.0042)and HBV DNA(r=0.6832,P=0.0205)levels in patients with HBsAg loss.The sPD-1 levels were negatively correlated with HBsAg levels in all patients after 12 mo of antiviral treatment,especially at 24(r=-0.356,P=0.0497)and 48(r=-0.4783,P=0.0037)mo.After 6 mo of antiviral treatment,the AUC of sPD-1 for HBsAg loss was 0.898(P=0.000),whereas that of HBsAg was 0.617(P=0.419).The cut-off value of sPD-1 was set at 2.34 log pg/mL;the sensitivity and specificity were 100%and 66.7%,respectively.CONCLUSION The sPD-1 levels at 6 mo can predict HBsAg loss after 144 mo of antiviral treatment.

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.

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.

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.

Hypophysitis induced by anti-programmed cell death protein 1 immunotherapy in non-small cell lung cancer:Three case reports

BACKGROUND Hypophysitis induced by programmed cell death 1 protein(PD-1)immune checkpoint inhibitors is rare and poorly described.We report three patients with non-small cell lung cancer who developed hypophysitis after anti-PD-1 immunotherapy.CASE SUMMARY Both case 1 and case 2 presented with common symptoms of fatigue,nausea,and vomiting.However,case 3 showed rare acute severe symptoms such as hoarse voice,bucking,and difficulty in breathing even when sitting.Following two cycles of immunotherapy in case 3,the above severe symptoms and pituitary gland enlargement were found on magnetic resonance imaging at the onset of hypophysitis.These symptoms were relieved after 10 d of steroid treatment.Case 3 was the first patient with these specific symptoms,which provided a new insight into the diagnosis of hypophysitis.In addition,we found that the clinical prognosis of patients with hypophysitis was related to the dose of steroid therapy.Case 3 was treated with high-dose hormone therapy and her pituitary-corticotropic axis dysfunction returned to normal after more than 6 mo of steroid treatment.Cases 1 and 2 were treated with the low-dose hormone,and dysfunction of the pituitary-corticotropic axis was still present after up to 7 mo of steroid treatment.CONCLUSION The clinical symptoms described in this study provide a valuable reference for the diagnosis and treatment of immune-related hypophysitis.

Programmed cell death protein-1 inhibitor combined with chimeric antigen receptor T cells in the treatment of relapsed refractory non- Hodgkin lymphoma: A case report

BACKGROUND Chimeric antigen receptor T cell(CART)therapy has benefited many refractory lymphoma patients,but some patients experience poor effects.Previous studies have shown that programmed cell death protein-1(PD-1)inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARY A 61-year-old male presented with 15-d history of diarrhea and lower-limb edema.A large mass was detected in the pelvis,and pathology indicated non-Hodgkin diffuse large B-cell lymphoma.After three cycles of the R-CHOP chemotherapeutic regimen,the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine.Pathological examination of the nodules indicated DLBCL again.The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma.We recommended CAR-T cell treatment.Before treatment,the patient’s T cell function and expression of immune detection points were tested.Expression of PD-1 was obviously increased(52.7%)on cluster of differentiation(CD)3+T cells.The PD-1 inhibitor(3 mg/kg)was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide.CAR-CD19 T cells of 3×10^(6)/kg and CAR-CD22 T cells 1×10^(6)/kg were infused,respectively.The therapeutic effect was significant,and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable.Presently,the patient has been disease-free for more than 12 mo.CONCLUSION This case suggests that the combination of PD-1 inhibitors and CAR-T cellsimproved therapeutic efficacy in B-cell lymphoma.

Nursing care of a patient with programmed cell death protein-1 immunotherapy-related myocarditis combined with coronary heart disease

This report introduced and summarized the nursing care experience for a senior patient with lung cancer and developed programmed cell death protein 1(PD-1)immunotherapy-related myocarditis combined with coronary heart disease(CHD)after receiving said treatment.In this case,immune myocarditis with CHD occurred shortly after implementing the PD-1 immunotherapy,yet the patient presented no clinical symptoms.Frequent nursing attention and close observation are so required for monitoring the patient’s status and updating the physicians for a swift control of the myocarditis.For this case,nursing care procedures vital for the successful recovery of the patient included condition observation,position management,pre-and postcoronary angiography care,infection prevention,hemorrhage prevention,venous access port maintenance,pain care,trachea care,psychological care,diet care,environment management,and health education.After receiving effective,successful treatment and care,the patient was discharged after 13 days of treatment with generally satisfying overall conditions.

Pivotal role of long non-coding ribonucleic acid-X-inactive specific transcript in regulating immune checkpoint programmed death ligand 1 through a shared pathway between miR-194-5p and miR-155-5p in hepatocellular carcinoma

BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade.Non-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic modulation.Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1.Recently,nutraceutical therapeutics in cancers have received increasing attention.Thus,it is interesting to study the impact of oleuropein on the respective study key players.AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,respectively.In addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1.HCC and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 expression.To study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried out.RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and XIST.MALAT-1 and XIST were predicted to target PD-L1 mRNA.PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely detected.MiR-194 induced expression elevated the expression of PD-L1,XIST and MALAT-1.However,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MALAT-1 expression.Knockdown of XIST did have an impact on PD-L1 expression;however,following knockdown of the negative regulator of X-inactive specific transcript(TSIX),PD-L1 expression was elevated,and abolished MALAT-1 activity.Upon co-transfection of miR-194-5p with siMALAT-1,PD-L1 expression was elevated.Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression.Upon co-transfection of miR-194 with siTSIX,PD-L1 expression was upregulated.Interestingly,the same PD-L1 expression pattern was observed following miR-155-5p cotransfections.Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1,XIST,and miR-155-5p,upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC,have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.

炎调方通过PD-1/PD-L1通路抑制脓毒症大鼠T淋巴细胞衰竭的实验研究

目的研究炎调方对脓毒症大鼠T淋巴细胞及T淋巴细胞表面表面程序性死亡蛋白(PD-1)、程序性死亡蛋白配体(PD-L1)表达的影响。方法SD大鼠(雄性)分为正常组、假手术组、模型组和炎调方组。盲肠结扎穿孔(CLP)制备脓毒症大鼠模型,于造模后12、24、48、72 h采集外周血处死大鼠(每个时间点各5只大鼠),采用流式细胞分析法测定CD3^(+)、CD4^(+)、CD8^(+)比例;双抗体夹心酶联免疫吸附法(ELISA)测定CD4^(+)及CD8^(+)表面PD-1、PD-L1表达水平。结果白介素-6(IL-6)在脓毒症模型组12 h分泌达到高峰后逐渐下降,降钙素原(PCT)在模型组24 h达到高峰后逐渐下降;炎调方组在12 h降低IL-6的水平(P<0.05),24 h时明显降低IL-6、PCT的水平(P<0.01)。模型组CD3^(+)、CD4^(+)、CD8^(+)比例早期分泌开始减少,48 h分泌达最低点(P<0.01);炎调方组在48 h时可升高CD3^(+)、CD4^(+)、CD8^(+)比例,提高CD4^(+)/CD8^(+)的比值而具体调节T细胞活化和增殖的功能。模型组CD4^(+)、CD8^(+)表面PD-1、PD-L1表达水平早期24 h即表达增多(P<0.01),72 h表达最多;炎调方组24 h时即可抑制PD-1、PD-L1的表达水平而具体改善T细胞衰竭的作用。CD4^(+)的比例与CD4^(+)表面PD-1、PD-L1的表达呈负相关(P<0.01);CD8^(+)比例与CD8^(+)表面PD-1、PD-L1的表达呈负相关(P<0.01)。结论脓毒症早期48 h内即出现了T细胞活化和增殖的功能衰竭引起的T细胞免疫抑制。炎调方能在脓毒症早期改善T细胞活化和增殖的功能,其机制可能与抑制PD-1/P-L1通路有关。

血清OPN、sPD-L1、miR-370在急性髓系白血病中的表达及与危险分层的关系

目的:分析血清骨桥蛋白(OPN)、可溶性程序性死亡因子配体-1(sPD-L1)、微小RNA-370(miR-370)在急性髓系白血病(AML)中的表达及与危险分层的关系。方法:选取2021年11月—2023年2月本院诊治的79例AML患者作为研究对象,根据相关标准分为低危组(n=26)、中危组(n=39)及高危组(n=14)。比较3组治疗前后血清OPN、sPD-L1、miR-370、白细胞计数(WBC)、血红蛋白(Hb)水平,采用Pearson分析血清OPN、sPD-L1、miR-370水平与WBC、Hb水平相关性,采用受试者工作特征曲线(ROC)分析治疗前血清OPN、sPD-L1、miR-370水平联合检测对AML患者危险分层情况的诊断价值。结果:3组治疗前后血清OPN、sPD-L1、miR-370、WBC水平比较:低危组<中危组<高危组(P<0.05);血清Hb水平比较:低危组>中危组>高危组(P<0.05);治疗前后血清OPN、sPD-L1、miR-370水平与WBC水平呈正相关(治疗前:r=0.637、0.629、0.661,治疗后:r=0.432、0.422、0.544,P<0.05),与Hb水平呈负相关(治疗前:r=-0.655、-0.648、-0.646,治疗后:r=-0.519、-0.507、-0.438,P<0.05);治疗前血清OPN、sPD-L1、miR-370联合检测诊断AUC为0.942,高于单一检测(P<0.05)。结论:血清OPN、sPD-L1、miR-370水平与AML患者病情程度、分层情况密切相关,可为临床诊疗提供参考。

HBV相关慢加急性肝衰竭患者sPD-1/sPD-L1与T细胞的相关性分析

目的:探讨乙型肝炎病毒(hepatitis B virus,HBV)相关慢加急性肝衰竭(acute-on-chronic liver failure,ACLF)患者病程中可溶性程序性死亡蛋白1(soluble Programmed cell death protein1,sPD-1)、可溶性程序性死亡蛋白配体-1(soluble Programmed cell death ligand1,sPD-L1)、T淋巴细胞、白细胞介素-10(interleukin-10,IL-10)和转化生长因子-β(transforming growth factor-β,TGF-β)的表达水平及各指标间的相关性。方法:收集71例确诊为HBV-ACLF患者的资料及外周血标本,根据研究对象28 d的随访结果,分为存活组40例和死亡组31例。采用流式细胞术检测研究对象外周血CD4+T及CD8+T细胞的比例。采用流式液相多重蛋白定量(cytometric bead array,CBA)技术检测sPD-1和sPD-L1的表达。采用酶联免疫吸附实验(enzyme-linked immunosorbent assay,ELISA)检测TGF-β和IL-10的表达。Pearson法分析HBVACLF患者血清中sPD-1/sPD-L1与患者MELD评分、T细胞及细胞因子水平的相关性。结果:死亡组外周血及血清中CD4+T细胞百分比、sPD-1、sPD-L1、IL-10和TGF-β高于存活组,而CD8+T细胞百分比低于存活组(P均<0.05)。经相关性分析显示,sPD-1水平与IL-10、TGF-β和CD4+T细胞百分比呈正相关,与CD8+T细胞百分比呈负相关。sPD-L1水平与终末期肝病模型(model for end-stage liver disease,MELD)评分、IL-10、TGF-β和CD4+T呈正相关,与CD8+T细胞比例呈负相关(P均<0.05)。结论:sPD-1/sPDL1可能参与了HBV-ACLF发生、发展过程中的免疫应答,通过综合考虑患者sPD-1和sPD-L1水平可以为HBV-ACLF患者开展及时有效的治疗提供一定的参考。

南京地区健康人群血清可溶性程序性死亡蛋白-1参考区间的建立

目的探讨健康人群血清可溶性程序性死亡蛋白-1(soluble programmed cell death protein-1,sPD-1)水平及其影响因素,初步建立南京地区健康人群血清sPD-1水平的参考区间。方法本研究纳入2023年5月至9月在南京鼓楼医院及句容人民医院进行体检的健康人群375例,其中男性194例,女性181例。留取健康人群的血清标本,采用基于新型探针生物传感器的全自动荧光免疫分析法(tests-on-probes,TOP法)检测血清sPD-1水平,并分析性别、年龄及其他实验室指标对sPD-1的影响;采用非参数法计算总体及不同年龄段健康人群血清sPD-1水平的参考区间。结果健康人群血清sPD-1水平为108.82(92.80,134.95)pg/mL,男性和女性健康人群血清sPD-1水平差异无统计学意义(P>0.05)。进一步将健康人群按照年龄分为<65岁和≥65岁2组,其血清sPD-1水平分别为106.65(90.35,130.60)pg/mL,113.20(95.60,144.83)pg/mL,组间差异有统计学意义(P=0.014);而将健康人群根据年龄分成3组(<40岁,40~64岁,≥65岁)时,其血清sPD-1水平分别为112.00(98.68,137.23)pg/mL,99.07(82.38,119.60)pg/mL,113.20(95.60,144.83)pg/mL,3组间差异亦有统计学意义(P<0.001)。多因素线性回归分析显示,γ-谷氨酰基转移酶(γ-glutamyl transpeptidase,GGT)是健康人群血清sPD-1水平的影响因素。根据临床与实验室标准协会(Clinical and Laboratory Standards Institutes,CLSI)C28-A3文件推荐的非参数法计算sPD-1参考区间,健康人群总体血清sPD-1水平的参考区间(第2.5%~97.5%百分位的浓度范围)为66.7~214.7 pg/mL;将健康人群分为<40岁、40~64岁、≥65岁3个年龄段,其对应的血清sPD-1在第2.5%~97.5%百分位的浓度范围分别为71.9~202.7 pg/mL、59.4~220.0 pg/mL、69.6~229.0 pg/mL。结论本研究初步建立了南京地区血清sPD-1健康人群以及分为3个年龄段的参考区间。

PD-1抑制剂联合一线化疗方案对晚期驱动基因阴性肺腺癌的效果及安全性分析

目的探讨程序性细胞死亡蛋白-1(PD-1)抑制剂联合一线化疗方案治疗晚期驱动基因阴性肺腺癌的效果及安全性。方法回顾性收集2019年1月至2021年12月收治的60例晚期驱动基因阴性的肺腺癌患者病历资料,依据治疗方式不同分组,将30例接受培美曲塞、顺铂联合PD-1抑制剂(信迪利单抗)治疗的病历资料纳入观察组另30例接受培美曲塞联合顺铂治疗的病历资料纳入对照组。对比2组患者治疗前、治疗30 d时2组临床疗效[客观缓解率(ORR)、疾病控制率(DCR)]、免疫功能[CD_(4)^(+)、CD_(8)^(+)、CD_(4)^(+)/CD_(8)^(+)]、肿瘤标志物[癌胚抗原(CEA)、细胞角蛋白19片段(CYFRA21-1)]、不良反应[恶心、粒细胞减少、肝功能异常、甲状腺功能异常、肺炎、皮疹、血小板降低]。结果观察组ORR显著高于对照组,差异有统计学意义(P<0.05);2组DCR比较差异无统计学意义(P>0.05);治疗后,观察组CD_(4)^(+)、CD_(4)^(+)/CD_(8)^(+)水平高于治疗前,且高于对照组(P<0.05);治疗后,2组CYFRA21-1、CEA水平均下降,且观察组低于对照组(P<0.05)。观察组甲状腺功能异常、肺炎、皮疹等发生例数显著多于对照组,差异有统计学意义(P<0.05)。结论PD-1抑制剂联合化疗一线治疗可有效改善晚期驱动基因阴性肺腺癌患者免疫功能,并降低肿瘤标志物水平,疗效确切。

靶向程序性细胞死亡蛋白配体-1多肽类放射性核素标记分子探针研究进展

程序性细胞死亡蛋白配体-1(PD-L1)是一个重要的免疫检查点分子,在调节机体免疫反应方面发挥重要作用。临床研究表明,肿瘤组织中PD-L1的表达水平与免疫检查点抑制剂疗效密切相关。由于肿瘤的时空异质性,临床上常用的免疫组织化学方法不能全面准确地反映患者体内PD-L1的表达水平,而核医学分子影像技术可在分子水平上无创、实时、动态、可视化监测机体内PD-L1的表达水平。本文主要针对靶向PD-L1多肽类放射性分子探针的研究进行综述,为寻找新型免疫成像的多肽类分子探针及免疫治疗适宜患者的筛选和疗效评估等提供指导。

血清sPD-1、PTX3水平与急性淋巴细胞白血病患儿临床病理特征的相关性分析

目的 探索急性淋巴细胞白血病(ALL)患儿的血清可溶性程序性死亡受体-1(sPD-1)和正五聚蛋白-3(PTX3)水平与患者临床病理特征的相关性。方法 选取2020年7月至2022年6月该院确诊的ALL患儿91例作为实验组,选择同期86例在本院收治的非恶性血液病患儿作为对照组,采用酶联免疫吸附试验(ELISA)测定血清sPD-1、PTX3水平,并分析二者与ALL患儿临床病理特征的关系;多元Logistic回归分析发生ALL的影响因素;受试者工作特征(ROC)曲线分析血清sPD-1、PTX3水平对ALL的诊断价值。结果 与对照组相比,实验组中血清sPD-1、PTX3水平均显著升高,差异有统计学意义(P<0.05);随着白细胞计数、原始细胞比例、不同危险(Risk)分层指标的升高,ALL患儿血清sPD-1、PTX3水平随之升高,随着血小板计数、血红蛋白水平指标的升高,血清sPD-1、PTX3水平随之降低,差异均具有统计学意义(P<0.05);ROC曲线下面积(AUC)显示,sPD-1单独诊断ALL的AUC为0.760(95%CI:0.689~0.831),截断值为21.926 pg/mL,PTX3单独诊断ALL的AUC为0.749(95%CI:0.672~0.826),截断值为3.168 ng/mL,二者联合诊断ALL的AUC为0.881(95%CI:0.833~0.928),二者联合诊断的AUC显著大于sPD-1单独诊断的AUC(Z=2.797,P=0.005),PTX3单独诊断的AUC(Z=2.883,P=0.004);Logistic回归分析显示血清sPD-1、PTX3水平是发生ALL的影响因素(P<0.05)。结论 ALL患儿血清sPD-1、PTX3水平均显著上升,血清sPD-1、PTX3水平是ALL发生的危险性因素,二者联合检测对ALL患儿的临床判断提供极大帮助。

基于PD-L1蛋白表达水平的胃癌免疫治疗专家共识(2023年版)

以程序性死亡蛋白-1(programmed death protein-1,PD-1)抑制剂为代表的免疫检查点抑制剂在胃癌中显示良好疗效,逐步改变晚期胃癌的治疗格局。对于程序性死亡蛋白配体-1(programmed death-ligand 1,PD-L1)高表达的患者,PD-L1单抗的治疗效果更为优异,且与PD-L1蛋白表达水平呈正相关。而对于PD-L1阴性或低表达这类免疫治疗非优势人群,以PD-1单抗为基础的用药方案疗效有限,尝试双特异性抗体、ADC等不同药物的联合也是一种趋势。为了精准指导临床实践,中国抗癌协会胃癌专业委员会组织国内胃癌领域专家进行多轮讨论,系统汇总国内外最新指南和循证证据,并结合我国临床实际,从病理检测、晚期治疗以及围术期治疗3个方面制订了本专家共识,旨在提高胃癌诊治的科学性和规范性,尤其是指导基层医生对免疫治疗的选择和应用。

PD-L1、miR-29a、miR let-7a对三阴性乳腺癌患者预后的评估价值分析

目的探讨程序性死亡蛋白配体-1(PD-L1)、微小RNA-29a(miR-29a)、微小RNA let-7a(miR let-7a)在三阴性乳腺癌(TNBC)患者预后评估中的临床价值。方法将67例TNBC患者作为观察组,同期收治的67例乳腺良性肿物患者作为对照组。所有患者均采集标本送检,测定PD-L1表达水平,并采集5 ml空腹静脉血,采用实时荧光定量PCR法测定miR-29a、miR let-7a表达情况,分析PD-L1、miR-29a、miR let-7a与其临床病理特征及预后的关系。结果观察组PD-L1阳性率、miR-29a表达量、miR let-7a表达量高于对照组,PD-L1阳性组临床分期Ⅲ期、淋巴结转移率高于PD-L1阴性组,临床分期Ⅲ期、淋巴结转移患者miR-29a、miR let-7a表达水平高于临床分期Ⅰ~Ⅱ期、无淋巴结转移患者,差异有统计学意义(P<0.05);67例患者随访3年后存活率为59.70%(40/67);PD-L1阳性患者存活率低于PD-L1阴性患者,存活者miR-29a、miR let-7a表达水平低于死亡组,差异有统计学意义(P<0.05)。结论PD-L1、miR-29a、miR let-7a在TNBC中呈高表达,与临床分期、淋巴结转移关系密切,且高表达患者存活率更低,可作为临床评估预后的重要指标。

肝细胞癌肿瘤微环境细胞毒性T细胞PD-1的表达及其临床意义

目的探讨程序性细胞死亡蛋白1(PD-1)在肝细胞癌(HCC)肿瘤微环境细胞毒性T细胞中的表达及其临床意义。方法回顾性选取2012年1月至2020年12月入复旦大学附属中山医院青浦分院接受手术治疗的HCC患者344例为研究对象,手术切除HCC患者的癌组织,免疫组织化学双染色法检测PD-1的表达,依据PD-1的表达中位数水平分为PD-1高表达和PD-1低表达,分析PD-1表达与临床病理参数的相关性,采用Kaplan-Meier方法计算总生存率和无进展生存率并绘制生存曲线,采用多因素Cox回归分析HCC的预后影响因素。结果PD-1表达于HCC肿瘤浸润淋巴细胞的细胞膜和(或)细胞质上,肿瘤浸润淋巴细胞中PD-1的高表达率为43.9%(151/344);HCC肿瘤组中PD-L1的阳性表达率为21.8%(75/344);HCC肿瘤浸润免疫细胞中PD-L1的阳性表达率为47.1%(162/344);肿瘤浸润CD8^(+)T细胞高密度率为45.3%(156/344)。PD-1高表达与肿瘤组织学分级、肿瘤细胞PD-L1表达、CD8^(+)T淋巴细胞PD-L1表达、CD8^(+)T淋巴细胞密度有关(P<0.05)。PD-1高表达患者的总生存率为80.81%,明显低于PD-1低表达患者(88.95%),差异有统计学意义(P<0.05)。PD-1高表达患者的无病生存率为67.44%,明显低于PD-1低表达患者(84.30%),差异有统计学意义(P<0.05)。多因素Cox回归分析结果显示,肿瘤细胞PD-L1表达、肿瘤浸润免疫细胞PD-L1表达、CD8^(+)T淋巴细胞密度均为影响肝细胞癌患者预后的危险因素(P<0.05)。结论CD8^(+)T淋巴细胞中PD-L1具有较高的表达率,CD8^(+)T细胞PD-1高表达与肿瘤组织学分级、肿瘤细胞PD-L1表达、CD8^(+)T淋巴细胞PD-L1表达、CD8^(+)T淋巴细胞密度、总生存率和无病生存率显著相关,可作为HCC患者辅助诊断和预测预后的指标之一。

LRP1B对Lewis细胞增殖、迁移、侵袭及免疫微环境的影响

目的探讨LRP1B基因对Lewis肺癌细胞增殖、迁移、侵袭及免疫微环境的影响。方法采用TCGA数据库分析LRP1B基因在肺癌及其他癌种中的表达情况。使用CRISPR/Cas9技术构建LRP1B敲除的Lewis细胞(KO组),选择野生型Lewis细胞作为对照组(NC组)。免疫印迹法验证上述2组细胞中LRP1B蛋白的表达。采用CCK-8法检测细胞存活率,划痕实验和细胞侵袭实验检测细胞的迁移和侵袭能力。将制备好的KO组或NC组细胞悬液注射到C57BL/6小鼠右侧腋窝皮下,分别标记为KO组小鼠和NC组小鼠,观察小鼠皮下移植瘤生长情况,流式细胞术检测荷瘤小鼠移植瘤中骨髓源性抑制细胞(MDSC)和CD8^(+)T细胞浸润的变化,免疫组化法检测程序性死亡受体-1(PD-1)及其配体(PD-L1)的水平。结果LRP1B基因在肺腺癌和肺鳞癌组织中的表达水平明显高于癌旁组织。与NC组细胞相比,LRP1B基因敲除后KO组细胞的增殖、迁移和侵袭能力均显著增加(P<0.05)。与NC组小鼠相比,KO组小鼠形成的移植瘤体积明显增加(P<0.05);移植瘤中MDSC比例显著增加、CD8^(+)T细胞比例减少,PD-L1、PD-1表达水平显著增加(P<0.05)。结论LRP1B基因敲除可促进Lewis肺癌细胞的增殖、迁移和侵袭能力,促进PD-L1、PD-1表达。

PD-1抑制剂预防肝细胞癌消融术后复发的临床研究

目的探讨程序性细胞死亡受体-1(PD-1)抑制剂用于肝细胞癌(HCC)消融术后预防复发的有效性和安全性。方法前瞻性选择2021年1月至2023年3月在首都医科大学附属北京佑安医院行肝动脉栓塞(TAE)序贯局部消融术(微波消融或射频消融)治疗后达到完全消融的HCC患者63例,根据患者意愿将患者非随机分配至试验组(n=31)或对照组(n=32),试验组术后接受PD-1抑制剂辅助治疗(卡瑞利珠单抗治疗200 mg,每3周1次),对照组无辅助治疗。Kaplan-Meier法绘制累计复发率曲线,Log-rank检验比较两组生存率差异;Cox回归分析得出影响HCC患者局部消融术后无复发生存期(RFS)的独立危险因素。结果两组治疗后随访2~15个月,中位随访8个月。试验组复发率明显低于对照组(41.94%vs 68.75%,χ^(2)=4.59,P=0.03)。试验组中1~2级免疫相关不良事件发生率为92.59%(25/27),≥3级为7.41%。肿瘤最大径(HR=0.49,95%CI 0.25-0.98,P<0.05)与抗PD-1辅助治疗(HR=0.41,95%CI 0.20-0.85,P<0.05)是HCC患者消融术后RFS的独立影响因素(P<0.05)。结论本研究的短期结果表明,PD-1抑制剂用于HCC根治性消融术后的肿瘤预防复发安全、有效。