CN118059094A - Nod2抑制剂在制备治疗胃癌药物中的用途 - Google Patents
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Abstract
本发明公开了NOD2抑制剂在制备治疗胃癌药物中的用途。本发明基于体外基础实验的结果:感染HP的GC患者中NOD2表达显著升高,NOD2高表达组免疫治疗应答率低,术后生存率低;进而通过构建胃幽门螺旋杆菌感染的原位小鼠GC模型,进行了动物体内实验,结果表明,联合NOD2抑制剂和免疫检查点抑制剂可以显著提高HP+GC免疫治疗的疗效,NOD‑2抑制剂可显著抑制HP的促瘤作用,并显著提高了小鼠生存率;因此,本发明为胃癌免疫治疗提供了一种联合NOD2抑制剂和免疫检查点抑制剂的药物治疗方案,其具有较好的临床应用前景。
Description
技术领域
本发明涉及NOD2抑制剂在制备治疗胃癌药物中的用途,属于生物医药技术领域。
背景技术
胃癌(Gastric cancer,GC)是世界范围内常见的恶性肿瘤,在所有癌症中发病率排名第五,死亡率排名第三。手术、化疗和放疗是传统胃癌的治疗方式。但是目前胃癌的预后一般依旧较差,5年平均生存率低于20%。
免疫治疗(抗PD-1治疗)已成为治疗胃癌的一种新兴方法,颇具前景。然而,目前免疫治疗的应答率仍然不理想,大约在10%到26%之间。既往的研究显示幽门螺杆菌(HP)可能是影响免疫治疗的疗效的重要原因之一。HP幽门螺杆菌感染,导致胃组织持续炎症,进而导致免疫耐受的建立。这种免疫耐受通过上调PD-L1表达和骨髓源性抑制细胞(MDSCs)的浸润,或抑制CD8+T细胞的抗肿瘤反应,进一步阻碍了抗PD-1治疗的疗效。但是传统的抗HP治疗可能导致菌群失衡,降低免疫治疗的效果,而HP诱导的GC免疫逃避的机制依旧未能完全揭示,这阻碍了人们通过抑制HP诱导的免疫抑制,来提升免疫治疗疗效,改善患者预后。
核苷酸结合寡聚化结构域(NOD)样受体(NLRs)是一组重要的细胞内宿主模式识别受体(Host pattern recognition receptor,PRRs),能够识别细胞环境中的各种微生物。其在介导微生物识别和应答中起着至关重要的作用。既往的研究显示表明NLRs在HP感染期间对细胞内成分的识别和免疫耐受的调节中可能发挥关键作用。但是目前未见通过NLRs(NOD2抑制剂)增加免疫治疗作用于HP+GC的方法,以增强免疫治疗胃癌疗效的相关报道。
发明内容
本发明的目的是:针对幽门螺杆菌感染的胃癌采用免疫治疗应答率不高的技术问题,本发明提供NOD2抑制剂在制备治疗胃癌药物中的用途。
为了实现上述目的,本发明提供了NOD2抑制剂联合免疫检查点抑制剂在制备治疗抗胃癌药物中的应用,所述胃癌指的是同时伴随有胃幽门螺旋杆菌感染。
优选地,所述药物包括有效成分和药学上可接受的载体,所述有效成分为NOD2抑制剂和免疫检查点抑制剂。
优选地,所述NOD2抑制剂为GSK717,其CAS号为1595278-21-9,化学结构式如下所示:
优选地,所述的免疫检查点抑制剂为PD-L1抑制剂。
优选地,所述药物的剂型为片剂、胶囊剂、散剂、颗粒剂、注射剂或口服液体制剂。
优选地,所述药物的给药方式为(内镜下)肿瘤局部注射。
与现有技术相比,本发明的有益效果在于:
本发明通过体外实验发现感染HP的GC患者中NOD2表达显著升高,这表明NOD2的表达可能在胃癌发展的免疫微环境中起到重要作用,通过抑制NOD2的表达并联合免疫治疗可能可以提高胃癌的疗效,进一步的培养实验结果表明,NOD2抑制剂的使用可以有效地增加了抗肿瘤免疫反应,而NOD2的激活促进了胃癌的发展;进而构建了胃幽门螺旋杆菌感染的原位小鼠GC模型,进行了动物体内实验,结果表明,联合NOD2抑制剂和免疫检查点抑制剂可以显著提高HP+GC免疫治疗的疗效;因此,本发明为胃癌免疫治疗提供了一种联合NOD2抑制剂和免疫检查点抑制剂的药物治疗方案,其具有较好的临床应用前景。
附图说明
图1:A.多重免疫荧光检测NOD2表达的IHC染色图;B.统计分析NOD2的表达情况与抗PD-1治疗的应答率之间的关系;C.比较NOD2高表达组与低表达组抗PD-1治疗的应答率;D.比较NOD2高表达组与低表达组的术后总生存期(OS)和无复发生存期(RFS);*:p<0.05;
图2:A.分析不同NOD2+TAM浸润程度组间总存活率的差异,每组n=40,统计分析采用对数秩检验;B.分析不同NOD2+TAM浸润程度组间血液中CEA和CA199以及TNM分期的差异,每组n=40,统计分析采用非配对双尾Student'st检验或Mann Whitney检验;*:p<0.05;***:p<0.001;
图3:A.共培养流程示意图;B.流式细胞仪检测不同共培养条件下CD8+T细胞的总比例和PD-1+TIGIT+亚型的比例;C.流式检测的定量分析结果,每组n=3,统计分析采用单因素方差分析和Dunnett多重比较检验;D.集落形成试验检测肿瘤细胞在不同的共培养条件下与PBMCs共培养后的增殖能力,无论是否经过抗PD-1治疗;E.对集落形成试验检测的结果进行定量分析,每组n=3,统计分析采用单因素方差分析和Dunnett多重比较检验;**:p<0.01;***:p<0.001;
图4:A.在胃幽门螺旋杆菌感染的原位小鼠GC模型中联合NOD-2抑制剂GSK717和抗PD-1单抗治疗的实验方案流程示意图;B.在各实验组和对照组中,肿瘤大小随时间的变化呈变化趋势(n=18),统计分析:单向方差分析和Dunnett多重比较检验;C.各实验组和对照组小鼠存活率的比较(n=18)统计学分析:Log-rank检验;*:p<0.05;***:p<0.001。
具体实施方式
为使本发明更明显易懂,兹以优选实施例,并配合附图作详细说明如下。
实施例1
实施材料:
60例胃癌合并慢性HP感染患者活检胃癌病例,来自复旦大学附属中山医院。所有患者均接受了抗PD-1治疗。活检样本接受福尔马林固定石蜡包埋(FFPE)。
实施方法:
多重免疫荧光染色分析:从FFPE样品中制备组织玻片,在微波炉中的EDTA(1mM,pH9.0)缓冲液中煮沸提取抗原。内源性过氧化物酶活性用3%的过氧化氢消灭,非特异性结合用阻断缓冲液(P0260,Beyotime)阻断。载玻片与一抗在4℃过夜或室温下孵育1.5h,然后二抗在室温下孵育1h。DAB染色呈阳性,苏木精染色呈反染。根据制造商的说明,使用Opal 6-Plex检测试剂盒(NEL821001KT,AKOYA生物科学公司)进行多重免疫荧光检测(图1A-B)。
总生存期(OS)定义为从手术到死亡的时间间隔。
无复发生存期(RFS)定义为手术至第一次复发的时间间隔.
使用mRECIST标准评估患者对治疗的反应。
实验结果:
HP感染的GC患者出现NOD2高表达,会降低抗PD-1治疗的应答(图1C)并降低患者的总生存期(图1D)。
实施例2
实施材料:
80例胃癌患者的组织微阵列样本及其伴随的临床、病理特征来自上海Superbiotek科技公司.
实施方法:
分析不同NOD2+TAM浸润程度组间总存活率的差异。每组n=40;统计分析采用对数秩检验。
分析不同NOD2+TAM浸润程度组间血液中CEA和CA199以及TNM分期的差异。每组n=40;统计分析:非配对双尾Student's t检验或Mann Whitney检验。
实验结果:
NOD2+TAMs富集组患者总生存率较低(图2A),TNM分期较高,肿瘤标志物CEA、CA199水平较高(升高1.5-2倍)(图2B)。
实施例3
实施材料:
HGC-27、AGS细胞系均来自Procell生命科学技术公司。所有细胞在rmi-1640(61870036,Gibco)培养基中,添加10%牛血清(10099141C,Gibco)和1%青霉素/链霉素(15140122,Gibco),37℃,5% CO2培养箱中培养。本实施例中使用的细胞系进行了常规鉴定,证实没有任何支原体污染。认证过程涉及STR分析的利用,细胞在低传代数下被利用。采用人PBMC全培养液(CM-H158,Procell)培养人外周血单核细胞源性巨噬细胞。提取的巨噬细胞在RPMI-1640培养基中培养,RPMI-1640培养基中添加10%胎牛血清和1%青霉素链霉素。小鼠骨髓源性巨噬细胞在添加10%胎牛血清和1%青霉素-链霉素的DMEM(11965092,Gibco)中培养,在37℃、5%CO2的培养箱中培养。然后用AGS或MFC上清液培养巨噬细胞以获得TAM。将幽门螺杆菌菌株PMSS1(MOI=100)和/或GSK717(10μg/kg,HY-136555,MCE)加入TAMs培养基中培养48h。细胞培养中使用的途径抑制剂:PI3K抑制剂taselisb 10nM(HY-13898,MCE),其用于抑制C1q。
实施方法:
1.根据Ficoll-Paque PREMIUM(17544202,GE Healthcare)方案分离巨噬细胞和共培养系统外周血单核细胞(PBMC),并使用hM-CSF(50ng/ml,216-MCC,R&D)刺激7-10天。收集非贴壁细胞,在ImmunoCultTM-XF T细胞扩增培养基(10981,StemCell)中培养,用ImmunoCultTMHuman CD3/CD28 T细胞激活剂(10971,StemCell)和30ng/ml IL-2(202-IL-050,R&D)按1:1比例过滤TAMs上清,培养3天。第3天,AGS或HGC-27与PBMCs按10:1的比例直接共培养于24孔板中。2天后,收集肿瘤细胞进行功能检测。实验流程如图3A所示。
2.流式细胞仪分析比较不同共培养条件下CD8+T细胞的总比例和PD-1+TIGIT+亚型的比例(图3A)。进行定量分析,每组n=3。统计分析:单因素方差分析和Dunnett多重比较检验(图3B)。其中,图3A、B的分组和结果为:(1).PBS+ISO:标准对照组;(2).HP+ISO:增加HP,可以降低CD8+T细胞,增加PD-1+TIGIT+亚型,从而降低抗PD-1治疗的疗效。(3).HP+GSK:HP基础上增加了GSK(NOD2抑制剂),可以挽救上述作用。(4).HP+Anti-C1q:HP基础上增加了抗C1q,也不存在上述(2)的变化,(5).PBS+C1q:在无HP的基础上,加用C1q表现出与加用HP类似的效果,(4)、(5)表明HP降低抗PD-1治疗的疗效,可能是通过C1q依赖的方式。其中,HP代表胃幽门螺旋杆菌。
3.集落形成试验显示肿瘤细胞在不同的共培养条件下与PBMCs共培养后的增殖能力,无论是否经过抗PD-1治疗(图3C)。进行定量分析,每组n=3。统计分析:单因素方差分析和Dunnett多重比较检验(图3D)。图3C、D的分组为:在上述分组的基础上都加用了一个抗PD-1治疗,同时增加一个标准对照:不加用PD-1治疗。分别在AGS与HGC-27两种胃癌细胞系中进行研究。
实验结果:
在HP+的GC细胞中使用NOD-2抑制剂GSK717可以提高抗PD-1治疗的疗效(图3C-D)。
实施例4
实施材料:
野生型C57BL/6J小鼠购自GemPharmatech(Nanjing,China),小鼠购自中国医学科学院血液研究所。
实施方法:
构建原位GC模型中,为了模拟人类幽门螺杆菌感染,制备了幽门螺杆菌PMSS1菌株,并在4周时接种小鼠。然后用100μl PBS皮下注射5×106个MFC-luc细胞。两周后,在无菌条件下解剖肿瘤,切成2mm3的立方体。然后将等大小的立方体植入6周龄小鼠的胃体中。植入3天后,皮下肿瘤小鼠随机分为4组。简单地说,每周瘤内注射抗PD-1抗体(10mg/kg,BE0146,BioXCell)或同型对照(Isotype Control,ISO)单抗(10mg/kg,BE0089,BioXCel)和/或GSK717(2.5mg/kg,HY-136555,MCE)3次,持续4周(图4A)。每周测量肿瘤体积2次,观察肿瘤大小变化,并观察小鼠80天的生存率。
实验结果:
在小鼠模型中使用NOD-2抑制剂GSK717可显著抑制HP的促瘤作用,NOD-2抑制剂GSK717与抗PD-1联合使用也提高了小鼠的总生存率(图4B-C)。
Claims (6)
1.NOD2抑制剂联合免疫检查点抑制剂在制备治疗抗胃癌药物中的应用,所述胃癌指的是同时伴随有胃幽门螺旋杆菌感染。
2.如权利要求1所述的应用,其特征在于,所述药物包括有效成分和药学上可接受的载体,所述有效成分为NOD2抑制剂和免疫检查点抑制剂。
3.如权利要求2所述的应用,其特征在于,所述NOD2抑制剂为GSK717,其CAS号为1595278-21-9,化学结构式如下所示:
4.如权利要求1所述的应用,其特征在于,所述的免疫检查点抑制剂为PD-L1抑制剂。
5.如权利要求1~4中任意一项所述的应用,其特征在于,所述药物的剂型为片剂、胶囊剂、散剂、颗粒剂、注射剂或口服液体制剂。
6.如权利要求1~4中任意一项所述的应用,其特征在于,所述药物的给药方式为肿瘤局部注射。
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