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.

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.

Refractory lymphoma treated with chimeric antigen receptor T cells combined with programmed cell death-1 inhibitor:A case report

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHL.Primary testicular(PT)lymphoma is an uncommon extranodal disease representing approximately 1%-2%of lymphoma.Approximately 30%–40%of patients are refractory to frontline therapy or relapse after complete remission.Refractory DLBCL responds poorly to other lines of chemotherapy,and experiences short-term survival.CASE SUMMARY We present a 41-year-old male patient who was diagnosed with PT-DLBCL.Further disease progression was observed after multiline chemotherapy.Chimeric antigen receptor T cells(CAR-T)therapy salvaged the patient.Unfortunately,a new mass was observed in the right adrenal area after six months.The patient was administered programmed cell death protein-1(PD-1)inhibitor therapy and maintained progression-free survival at more than 17 mo of follow-up.CONCLUSION Our findings support the potential benefit of CAR-T combined with PD-1 inhibitor therapies in this type of relapsed and refractory PT-DLBCL.

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.

Combination of carboxyamidotriazole and 1-Methyl-L-tryptophan has synergistic inhibtory effects on programmed death 1 expression

OBJECTIVE To evaluate whether the IDO1 inhibitor 1-methyl-L-tryptophan(1-MT)combine calcium influx inhibitor carboxyamidotriazole(CAI)could further enhance the suppression of programmed death 1(PD-1)in CD8^+T cells and investigate the curative effect of the combined use.METHODS CD8^+T cells were isolated from normal mice spleen by negative selection using magnetic cell separation.The isolated CD8^+T cells were cultured in RPMI 1640 medium containing 10%FBS and 100 U·mL^(-1)IL-2 and activated by the addition of anti-CD3 and anti-CD28(1 g·L^(-1) each mabs).CD8^+T cells were pretreated for 48 h with drug and the fluo-3 as a marker of intracellular calcium concentration was detected by flow cytometry.The calcineurin(Ca N)levels were assayed with ELISA in CD8^+T cells after 48 h incubation with 10μm CAI.The nuclear translocations of NFAT and AHR were detected by immunofluorescent staining after 48 h of drug treatment.The expression of PD-1 in CD8^+T cells was analyzed by flow cytometry.RESULTS Intracellular fluorescent intensity was markedly debase due to CAI treatment(P<0.01).Meanwhile,the changes of CaN content had a resembled correlation(P<0.01).Immunofluorescence experiment showed that after combination therapy the transfer of NFAT and AHR in nuclear substantially reduced.Flow cytometry revealed that after the combination caused a significant decrease in PD-1 expression in CD8^+T cells.CONCLUSION CAI and 1-MT could inhibit markedly the expression of PD-1 in CD8^+T cells by inhibiting the nuclear translocation of NFAT and AHR,respectively and the combination of them has synergetic effect.

急性髓系白血病患儿柔红霉素耐药与PD-L1蛋白表达相关

目的研究急性髓系白血病(AML)患儿柔红霉素(DNR)耐药与程序性死亡受体配体-1(PD-L1)蛋白表达的相关性。方法选取2016年1月至2022年12月郑州大学附属儿童医院收治的110例AML患儿骨髓样本作为研究组,以50名骨髓正常供体骨髓样本作为对照组。培养人AML细胞系HL60、THP-1、U-937、Molm-13,Western blot检测PD-L1蛋白表达量。构建LV-PD-L1-shRNA、LV-PD-L1-WT-OE慢病毒载体,分析PD-L1对Molm-13细胞DNR耐药的影响及机制。结果研究组PD-L1蛋白表达量高于对照组,AML细胞系中PD-L1蛋白表达量高于健康骨髓单个核细胞(BMMC)(P<0.05),PD-L1表达与AML患儿白细胞计数、骨髓原始细胞比率、预后危险分层、两个标准化学治疗方案后疾病缓解情况有关(P<0.05)。PD-L1高表达组总生存率低于PD-L1低表达组(P<0.05)。与LV-PD-L1-WT-OE组比较,LV-PD-L1-shRNA组PD-L1 mRNA表达量降低、细胞增殖活性降低、凋亡率升高(P<0.05),LV-PD-L1-shRNA可提高Molm-13细胞对DNR的敏感性。TCGA数据库分析显示,6-磷酸葡萄糖脱氢酶(G6PD)可能为PD-L1潜在的目标基因。结论PD-L1在儿童AML中高表达,与患儿化疗耐药有关,其可能通过调控G6PD引起DNR耐药。

ITP患者PD-1/PD-L1表达特点及其在Treg与Breg细胞之间的相互作用机制分析

目的探讨原发免疫性血小板减少症(ITP)患者细胞程序性死亡受体-1(PD-1)/细胞程序性死亡配体1(PD-L1)表达特点及其在调节性T细胞(Treg)、调节性B细胞(Breg)间的相互作用。方法选取2018年12月—2022年1月在我院治疗的ITP患者106例作为观察组,其中轻度患者32例,中度患者44例,重度患者30例。同时选取同期健康志愿者100例作为对照组。检测两组Treg细胞百分比、Breg细胞百分比、Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率等,同时分析观察组不同病情程度患者各指标差异。结果观察组Breg细胞百分比、Treg细胞百分比、TGF-β、IL-10和IL-4水平均明显低于对照组(P<0.05);观察组Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率、可溶性程序性细胞死亡蛋白-1(sPD-1)和IL-17水平均明显高于对照组(均P<0.05);两组可溶性程序性细胞死亡蛋白配体-1(sPD-L1)水平比较差异无统计学意义(P>0.05)。观察组重度患者Breg细胞百分比、Treg细胞百分比均明显低于轻度和中度患者(均P<0.05),而Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率均明显高于轻度和中度患者(均P<0.05)。Treg细胞表面PD-1阳性率与Breg细胞表面PD-L1阳性率呈正相关(r=0.446,P<0.05)。观察组治疗后Breg细胞百分比、Treg细胞百分比、TGF-β、IL-10和IL-4水平有所升高(P<0.05),而Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率、sPD-1和IL-17水平有所降低(P<0.05),治疗前后sPD-L1水平比较差异无统计学意义(P>0.05)。结论ITP患者Treg细胞表面PD-1和Breg细胞表面PD-L1阳性率明显升高,与患者病情严重程度呈正相关,同时Treg细胞表面PD-1和Breg细胞表面PD-L1表达之间存在相关性。

铜绿假单胞菌脓毒症患者程序性细胞死亡受体1/程序性细胞死亡配体1信号通路相关蛋白与短期临床预后的相关性分析

目的探讨程序性细胞死亡受体1/程序性细胞死亡配体1(PD-1/PD-L1)信号通路相关蛋白对铜绿假单胞菌(PA)脓毒症患者短期临床预后的影响。方法选择2021年1月—2023年6月宁夏医科大学总医院收治的122例PA脓毒症患者为研究对象,均根据脓毒症治疗指南和实际病情开展治疗。收集患者临床资料、治疗前慢性健康状况评分系统Ⅱ(APACHEⅡ)评分;治疗前抽取外周静脉血测定T淋巴细胞水平(CD3^(+)、CD4^(+)、CD8^(+))以及血清PD-1和PD-L1水平。结果122例PA脓毒症患者入住急诊重症监护室及其他科室后28 d存活101例(82.79%,存活组),死亡21例(17.21%,死亡组)。存活组与死亡组患者高血压比率、慢性阻塞性肺病比率、慢性肝病比率、APACHEⅡ评分、CD4^(+)、CD4^(+)/CD8^(+)、PD-1和PDL-1比较,差异有统计学意义(P<0.05)。单因素Logistic回归分析结果显示,基础疾病(高血压、慢性阻塞性肺病、慢性肝病)、APACHEⅡ评分、CD4^(+)/CD8^(+)、PD-1和PD-L1均是PA脓毒症患者短期生存的影响因素(P<0.01)。多因素Logistic回归分析结果显示,基础疾病(高血压、慢性阻塞性肺病、慢性肝病)、APACHEⅡ评分、PD-1和PD-L1均是PA脓毒症患者短期生存的影响因素(P<0.01)。结论PD-1/PD-L1信号通路对PA脓毒症患者的临床预后有影响,该通路相关蛋白表达上调可增加PA脓毒症患者短期临床预后不良的风险。

食管癌术后肾上腺危象1例并文献复习

目的:探讨肾上腺危象(AC)的临床特征及诊疗要点,减少临床工作中的漏诊、误诊、误治。方法:回顾性分析1例食管癌术后合并AC的临床资料,总结AC的临床诊治经过。结果:患者为49岁男性,因食管癌术后3周出现发热入院,存在吻合口瘘,给予多种抗菌药物长时间抗感染治疗效果不佳,即使瘘口愈合后仍间断高热、血压下降。患者偶用激素退热治疗后效果较好,但减量停用后患者逐渐乏力、卧床。查增强计算机断层扫描(CT)未见肿瘤复发,皮质醇、促肾上腺皮质激素(ACTH)明显偏低,结合术前曾应用程序性死亡受体1(PD-1)抑制剂,明确诊断为免疫治疗相关垂体炎,进而导致了AC,补充醋酸泼尼松片后好转出院。结论:AC是一种危急的内科急症,临床表现缺乏特异性,极容易漏诊、误诊、误治,临床医生应加强对本病的认识,从而达到早期诊断并能及时给予糖皮质激素治疗的目的。

PD1/PD-L1、中性粒细胞弹性蛋白酶、赖氨酰氧化酶在膀胱癌中的表达及其与膀胱癌预后的关系

目的探讨膀胱癌组织中程序性细胞死亡受体1(PD1)、程序性细胞死亡配体1(PD-L1)、中性粒细胞弹性蛋白酶(NE)、赖氨酰氧化酶(LOX)的表达水平及其表达差异与膀胱癌患者临床病理特征和预后的关系。方法选取2018年1月至2020年12月江西省人民医院收治的56例膀胱癌患者的癌组织作为研究对象,并记录患者的复发和死亡情况进行分析研究。采用免疫组织化学染色法检测PD1、PD-L1、NE、LOX的表达情况,分析PD1、PD-L1、NE、LOX与患者的病理特征和预后的关系。结果免疫组化结果显示PD1在肿瘤相关免疫细胞中存在表达(46/56);TNM分期T2-T3期、高级别肿瘤和出现淋巴结转移的患者PD1和PDL-1的表达阳性率均明显升高,差异有统计学意义(P<0.05)。NE与PD1、PDL-1的表达呈正相关(P<0.05);LOX与PD-L1、PDL-1的表达呈正相关(P<0.05)。PD1阳性表达患者3年无进展生存率为58.70%(27/46),PD-L1阳性表达患者3年无进展生存率为43.48%(10/23),不同PD1、PD-L1表达患者的3年无进展生存率比较差异有统计学意义(P<0.05)。结论膀胱癌组织中PD1、PD-L1表达增加可作为膀胱癌患者潜在的预后预测指标,有助于筛选术后复发的高危患者,并为膀胱癌的免疫学治疗提供新靶点。

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。

膀胱癌细胞内在程序性死亡受体-1受体功能对肿瘤的影响

目的:探讨膀胱癌细胞内在程序性死亡受体-1(PD-1)受体功能对肿瘤的影响。方法:选取2019年1月—2023年1月膀胱癌患者80例,采用免疫组织化学染色法检测膀胱癌患者癌组织以及距离肿瘤边缘3 cm的膀胱癌旁组织是否有PD-1表达;使用逆转录聚合酶链式反应技术对膀胱癌患者的癌组织以及距离肿瘤边缘3 cm的膀胱癌旁组织中PD-1 mRNA表达情况进行统计。并对其表达水平与临床病理学参数(年龄、性别、TNM分期、肿瘤分级等)进行相关性分析。结果:PD-1阳性表达率为63.75%(51/80),PD-1 mRNA阳性表达率为68.75%(55/80),而距离肿瘤边缘3 cm的膀胱癌旁组织均未见明显的PD-1和PD-1 mRNA的表达。通过临床相关性分析发现,PD-1的表达与膀胱癌临床TNM分期密切相关(P<0.05),但是其表达情况与膀胱癌患者的年龄、性别、肿瘤分级等无明显的相关性(P<0.05)。结论:膀胱癌患者癌组织中PD-1高度表达,在膀胱癌肿瘤发生发展的过程中具有一定的作用,可用来评估膀胱癌进展程度。

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。

多西他赛联合PD-1抑制剂对晚期非小细胞肺癌预后及血清MMP-9、TIMP-1水平的影响

目的探讨多西他赛联合程序性死亡受体1(PD-1)抑制剂对晚期非小细胞肺癌(NSCLC)预后及血清基质金属蛋白酶-9(MMP-9)、基质金属蛋白酶组织抑制剂-1(TIMP-1)水平的影响。方法将90例晚期NSCLC患者随机分为研究组和对照组,每组45例。对照组给予多西他赛和顺铂治疗,研究组在对照组治疗基础上给予PD-1治疗,3周为1个治疗周期,共治疗6个周期。比较2组治疗后客观缓解率(ORR)、疾病控制率(DCR)、无进展生存期(PFS)、总生存期(OS),观察2组治疗期间不良反应发生情况及治疗前后血清MMP-9、TIMP-1水平的变化。结果研究组治疗后DCR、PFS、OS显著高于对照组(P<0.05);治疗期间2组不良反应发生率比较差异无统计学意义(P>0.05);2组治疗后血清MMP-9、TIMP-1水平较治疗前显著降低(P<0.05),且研究组降低较对照组更为显著(P<0.05)。结论多西他赛联合PD-1抑制剂对晚期NSCLC具有较好的疗效和预后,能够降低血清MMP-9、TIMP-1水平,降低肺癌细胞侵袭转移的能力,安全性良好。

非小细胞肺癌患者抗PD-1/PD-L1治疗疗效及其肠道菌群特征分析

目的分析非小细胞肺癌(NSCLC)患者抗程序性死亡受体1(PD-1)/程序性死亡配体1(PD-L1)治疗疗效及其肠道菌群特征。方法将2020年1月至2022年1月新疆维吾尔自治区人民医院收治的81例NSCLC患者作为研究对象,根据患者免疫治疗应答情况,将患者分为无应答组及应答组,比较两组患者临床资料及肠道菌群分布差异,并采用Spearman相关性分析患者无进展生存期(PFS)与肠道菌群α多样性指标之间的相关性。结果应答组吸烟患者比例显著低于无应答组,差异有统计学意义(χ^(2)=4.648,P=0.031)。无应答组Chao1指数、ACE指数及香农-威纳指数患者低于应答组,辛普森多样性指数高于应答组,差异有统计学意义(P<0.05)。Chao1指数、ACE指数及香农-威纳指数与PFS呈正相关(r=0.526、0.579、0.539,均P<0.05),而辛普森多样性指数与PFS呈负相关(r=-0.867,P<0.001)。采用主坐标分析对肠道菌群β多样性结构进行分析,第一主成分贡献率为70.36%,第二主成分贡献率为16.63%。结论NSCLC患者肠道菌群多样性及分布与抗PD-1/PD-L1治疗有关,患者肠道菌群多样性越高,抗PD-1/PD-L1治疗越敏感。

西达本胺联合PD-1抑制剂对结直肠癌小鼠CD8+T细胞抗肿瘤功能的影响

目的探讨组蛋白去乙酰化酶(HDAC)抑制剂西达本胺联合程序性死亡受体-1(PD-1)抑制剂对结直肠癌小鼠模型(MC38-OVA)中CD8^(+)T细胞抗肿瘤功能的影响。方法动物实验:采用背部皮下注射法构建MC38-OVA结直肠癌小鼠模型。将MC38-OVA荷瘤小鼠随机分为对照组、西达本胺组、anti-PD-1组、西达本胺^(+)anti-PD-1组,每组20只。观察荷瘤小鼠肿瘤生长情况及存活率;采用流式细胞仪检测小鼠肿瘤微环境中CD8^(+)T细胞、CD8^(+)IFN-γ^(+)T细胞、OVA抗原特异性CD8^(+)T细胞的数量及比例,以及肿瘤组织内调节性T细胞(Treg)、髓系衍生抑制细胞(MDSC)、肿瘤相关巨噬细胞(TAM)的表达变化。细胞实验:采用流式细胞仪检测0、10、25、50、100、200 nmol/L西达本胺处理的CD8^(+)T细胞及MC38-OVA肿瘤细胞的凋亡情况。采用流式细胞计数法及Ki-67抗体标记法检测0、100 nmol/L西达本胺处理的CD8^(+)T细胞及MC38-OVA肿瘤细胞的增殖情况。取CD8^(+)T细胞,设置对照组、西达本胺组、anti-PD-1组与西达本胺^(+)anti-PD-1组,与MC38-OVA肿瘤细胞按预设效靶比共培养,采用流式细胞仪检测CD8^(+)T细胞的杀伤能力。经0、100 nmol/L西达本胺处理的CD8^(+)T细胞与相同数量的MC38-OVA肿瘤细胞共培养,采用流式细胞仪检测CD107a的表达情况。结果荷瘤小鼠肿瘤生长及生存分析结果显示,与对照组比较,西达本胺^(+)anti-PD-1组荷瘤小鼠肿瘤生长明显受抑(P<0.05),生存率明显增高(P<0.01)。西达本胺组、anti-PD-1组、西达本胺^(+)anti-PD-1组肿瘤浸润CD8^(+)T细胞比例及数量明显高于对照组(P<0.05)。西达本胺^(+)anti-PD-1组CD8^(+)IFN-γ^(+)T细胞、OVA抗原特异性CD8^(+)T细胞比例及数量明显高于对照组、西达本胺组、anti-PD-1组(P<0.05)。体外实验显示,西达本胺可增强CD8^(+)T细胞的杀伤能力及CD107a的表达(P<0.05)。结论西达本胺联合PD-1抑制剂可明显增强瘤内浸润CD8^(+)T细胞的数量及功能,诱导抗原特异性CD8^(+)T细胞数量增多,减轻小鼠肿瘤负荷。

比较TACE+微波消融+程序性死亡受体-1与TACE+微波消融治疗原发性肝癌

目的比较TACE+微波消融(MWA)+程序性死亡受体-1(PD-1)与TACE+MWA治疗原发性肝癌(PHC)的价值。方法回顾性纳入接受TACE+MWA+PD-1(观察组)或TACE+MWA治疗(对照组)的PHC患者各40例,比较组间基线资料、疗效和并发症。结果2组患者基线资料差异均无统计学意义(P均>0.05)。观察组与对照组客观缓解率(ORR)分别为90.00%和72.50%,疾病控制率(DCR)分别为97.50%和95.00%;组间差异均无统计学意义(P均>0.05)。观察组与对照组中位总生存期(OS)分别为30.80个月和15.70个月,中位无进展生存期(PFS)分别为23.35个月和6.80个月;观察组OS和PFS均长于对照组(P均<0.05)。组间并发症发生率差异均无统计学意义(P均>0.05),且均经相关对症治疗后好转。结论TACE+MWA+PD-1联合治疗PHC效果优于TACE+MWA。