CN117919416A - Slamf6的新用途 - Google Patents
Slamf6的新用途 Download PDFInfo
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- CN117919416A CN117919416A CN202311583703.7A CN202311583703A CN117919416A CN 117919416 A CN117919416 A CN 117919416A CN 202311583703 A CN202311583703 A CN 202311583703A CN 117919416 A CN117919416 A CN 117919416A
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- slamf6
- cells
- expression vector
- lentivirus
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Abstract
本发明公开了SLAMF6的新用途,属于生物医药技术领域。本发明的SLAMF6能促进Jurkat细胞迁移、减少Jurkat细胞凋亡、抑制MC38细胞增殖、增敏PD‑L1抗体治疗效果、增强CD8+T细胞对结直肠癌的杀伤活性。T细胞迁移试验结果表明,过表达SLAMF6可显著促进Jurkat细胞的迁移,减少了Jurkat细胞的凋亡;CCK‑8试验结果表明,过表达SLAMF6能够显著抑制MC38细胞的增殖;过表达SLAMF6联合抗PD‑L1可显著抑制肠癌细胞的增殖,适用于制备预防和/或治疗结直肠癌的药物;联合治疗组CD8+T细胞浸润最多。
Description
技术领域
本发明属于生物医药领域,涉及SLAMF6的新用途。
背景技术
结直肠癌(Colorectal cancer,CRC)作为全球第三大最常见的恶性肿瘤和第二大致命癌症。据报道,2020年全球估计有190万病例,占全球癌症发病率的10%,其中93.5万例死亡,占癌症死亡人数的9.4%。此外,结直肠癌的复发和转移严重影响患者的生存率,根据人类疾病发展的预测,在未来20年全球新增CRC病例将达到320万例。
目前,结直肠癌除了常规化疗和靶向治疗,免疫疗法已经成为新兴的治疗手段,免疫检查点抑制剂(ICIs:anti-programmed death-1,抗PD-1;anti-programmed death-ligand 1,抗PD-L1)已成为转移性CRC的一线药物,但是仅对20%不到的患者有效。抗PD-1或抗PD-L1抗体治疗肿瘤的主要原理是,通过阻断PD-1和PD-L1的结合恢复杀伤性T细胞的效应功能进而增强抗肿瘤免疫应答,是肿瘤学领域最重要的突破之一。因此,阐明ICIs反应和耐药性的关键因素以及增强CD8+T细胞的活化和浸润对于扩大肠癌免疫治疗获益人群、提升患者的预后和开发新的免疫治疗策略至关重要。
作为T细胞激活的重要调节因子,SLAMF6(CD352,Ly108或NTBA)广泛表达于T细胞、B细胞、NK细胞以及肿瘤细胞表面。它以“头碰头”的方式通过同型或异型细胞-细胞相互作用调节多种免疫细胞的激活和分化,并参与先天和适应性免疫反应的过程。以往研究发现,在黑色素瘤中SLAMF6能诱导T细胞激活和扩增,从而增强T细胞免疫表型和细胞毒性T细胞功能。例如,SLAMF6通过细胞质尾部的酪氨酸磷酸化招募SLAM相关蛋白(SLAM-associatedprotein,SAP),然后促进Src家族激酶Fyn的聚集以诱导T细胞活化。SLAMF6和CD3共定位在活化的T细胞上,并且在抗原刺激后,TCR信号被SLAMF6/SAP途径增强。Eisenberg等人证实可溶性SLAMF6细胞外结构域(Soluble ectodomain of SLAMF6,seSLAMF6)可促进SLAMF6受体的去磷酸化,并刺激CD8+T细胞释放更多的IFN-γ,增强敢杀伤作用。由此可见,SLAMF6在抗肿瘤免疫中发挥至关重要的作用。然而,在结直肠癌等大多数肿瘤中,SLAMF6对TMEs中T细胞活化的影响和促进免疫治疗的效果国内外尚未见报道。
发明内容
针对现有技术中存在的免疫治疗获益技术中的不足,本申请所要解决的技术问题是提供一种SLAMF6的新用途,SLAMF6作为药物靶点在增强抗PD-L1抗体治疗结直肠癌疗效中的应用。
为解决上述技术问题,本发明采用的技术方案为:
SLAMF6在制备用于具有以下一个以上功能的药物中的应用;
1)促进Jurkat细胞迁移,
2)减少Jurkat细胞凋亡,
3)抑制MC38细胞增殖,
4)增敏PD-L1抗体治疗效果,
5)增强CD8+T细胞对结直肠癌的杀伤活性。
SLAMF6慢病毒稳转细胞株的构建方法,其特征在于,包括:
1)构建慢病毒SLAMF6过表达载体;
2)将构建的慢病毒SLAMF6过表达载体转化到MC38细胞中;
3)培育筛选得到SLAMF6表达量显著提高的细胞株,即为SLAMF6慢病毒稳转细胞株。
所述慢病毒SLAMF6过表达载体为LV-SLAMF6。
所述慢病毒表达载体LV-SLAMF6的重组插入序列为ATGTTGTGGCTGTTCCAATCGCTCCTGTTTGTCTTCTGCTTTGGCCCAGGG AATGTA。
所述SLAMF6慢病毒稳转细胞株的构建方法构建得到的慢病毒表达载体LV-SLAMF6。
所述慢病毒表达载体LV-SLAMF6在促进Jurkat细胞迁移、减少Jurkat细胞凋亡中的应用。
所述慢病毒表达载体LV-SLAMF6在抑制MC38细胞增殖中的应用。
所述慢病毒表达载体LV-SLAMF6在增强CD8+T细胞对结直肠癌的杀伤活性中的应用。
所述慢病毒表达载体LV-SLAMF6在增敏PD-L1抗体治疗效果中的应用。
SLAMF6作为药物靶点在开发、筛选或制备用于预防和/或治疗结直肠癌药物中的应用。
优选的,所述药物增强或提高SLAMF6的表达和/或活性。
优选的,所述药物起到以下作用中的一项或多项:
1)调控结直肠癌免疫微环境达到抑制肿瘤生长的作用;
2)增强CD8+T细胞对结直肠癌的杀伤活性的作用;
3)增敏结直肠癌抗PD-L1抗体疗效的作用。
一种用于预防和/或治疗结直肠癌的联合用药物,所述联合用药物包括增强或提高的表达和/或活性的药物和抗PD-L1抗体。
优选的,所述联合用药物通过增强或提高SLAMF6的表达和/或活性来增强结直肠癌抗PD-L1抗体的疗效。
优选的,所述联合用药物起到以下作用中的一项或多项:
1)调控结直肠癌免疫微环境达到抑制肿瘤生长的作用;
2)增强CD8+T细胞对结直肠癌的杀伤活性的作用;
3)增敏结直肠癌抗PD-L1抗体疗效的作用。
相对于现有技术,本发明创造具有以下优势:
1)首次发现SLAMF6在肠癌组织中的表达量明显低于癌旁正常组织,并且其高表达提示肿瘤患者预后较好,且SLAMF6表达与CD8+T细胞的浸润成正相关。表明在结直肠癌中SLAMF6是重要的抑癌基因。
2)本发明发现在小鼠体内实验中,上调SLAMF6的表达联合免疫检查点抑制剂抗PD-L1可促进CD8+T细胞的活化和浸润,显著抑制肠癌细胞的增殖。提示SLAMF6是治疗结直肠癌的重要靶点。
附图说明
图1为SLAMF6在结直肠癌患者中的表达及预后分析图(A.使用TCGA数据库比较了SLAMF6在不同的肿瘤组织和癌旁组织中的表达水平;B.Westernblot用于检测SLAMF6在COAD、LIHC、STAD和癌旁组织中的表达;C.生存分析显示SLAMF6的表达对肠癌患者预后的影响;D-E.TCGA数据库分析肠癌中SLAMF6的mRNA在不同临床病理分期和免疫学亚型中的表达模式);
图2为在肠癌组织芯片中分析SLAMF6的表达与CD8+T细胞浸润的关系图(A.选取多重免疫荧光染色结果图的代表图像,比例尺:50μm;C.SLAMF6的表达与CD8+T细胞浸润的相关性分析,比例尺:50μm);
图3为慢病毒转染SLAMF6过表达载载体效率图(A.慢病毒转染SLAMF6过表达载体的荧光图像,比例尺:50μm;B-C.qRT-PCR和Westernblot技术检测了MC38细胞中SLAMF6的表达);
图4为过表达SLAMF6可增强对T细胞的招募作用图(A.T细胞迁移试验模型的构建(Transwell法);B-C.对迁移的Jurkat细胞进行数量和活力的检测;D.CCK-8试验证明过表达SLAMF6对MC38细胞增殖的影响);
图5为过表达SLAMF6联合抗PD-L1对小鼠体内肿瘤的抑制作用图(A-B.小鼠及小鼠肿瘤的图像;C.小鼠肿瘤的生长曲线;D-E.小鼠肿瘤体积和重量的比较);
图6为流式细胞术检测小鼠肿瘤组织中CD8+T细胞的浸润情况图。
具体实施方式
下列实施例仅用于说明本发明,但并不用来限定本发明的实施范围。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。下面结合实施例来详细说明本发明创造。
实施例1:SLAMF6在结直肠癌患者的肿瘤组织中的表达要低于癌旁正常组织,并且高表达SLAMF6的肠癌患者预后较好。
具体步骤如下:(1)收集来自南通大学附属医院结直肠癌患者组织标本,包括原位肿瘤组织和配对的癌旁组织。(2)取一部分组织标本放在1mL Trizol溶液中进行组织破碎,后续进行RNA和蛋白的提取,分别用qRT-PCR以Western blot检测SLAMF6mRNA水平和蛋白水平的表达。(3)另一部分组织放在4%多聚甲醛溶液中,通过固定、脱水、包埋、切片等方式制成石蜡切片,进行SLAMF6免疫组化的染色。(4)对TCGA结直肠癌数据库进行分析,比较SLAMF6的表达量在原位肿瘤和正常组织的差异,并分析其与患者预后的相关性。
结果如图1所示:TCGA数据库中SLAMF6在结肠腺癌和直肠腺癌中表达明显降低,Western blot分析显示COAD、LIHC和STAD的癌旁组织中SLAMF6的表达高于癌组织(图1A-B)。生存分析表明在肠癌中高表达SLAMF6预后较好(图1-C)。SLAMF6在肠癌中不同临床分期的表达有显著的差异性,表现出早期高表达,晚期低表达的特性(图1D-E)。
实施例2:SLAMF6的表达与CD8+ T细胞浸润的关系。
具体步骤如下:基于荧光的多重免疫组化技术标记组织切片中的SLAMF6与CD8A。(1)70℃烤箱中烤片1.5h,60℃烘箱中烘片1h;(2)组织切片置于二甲苯脱蜡(6min),100%酒精(5min),95%酒精(5min),70%酒精(5min),水化后用双蒸水冲洗;(3)在10%福尔马林中固定10min,用双蒸水冲洗;(4)抗原修复,组织切片在AR6缓冲液(AR600,Akoya)中使用微波加热进行抗原修复(微波100%功率2.5min,20%功率15min),自然冷却至室温,先使用双蒸水冲洗,再使用三乙醇胺缓冲盐水(TBST)冲洗;(5)免疫组化笔沿肿瘤组织边缘画圈,添加封闭液,封闭10min后弃去;(6)孵育一抗SLAMF6抗体(HPA051903,Atlas)4℃过夜,TBST冲洗3×2min;(7)二抗选用OpalTM聚合物HRP Ms+Rb(ARH1001EA,Perkin Elmer)室温孵育10min,TBST冲洗3×2min;(8)组织切片用6种TSA荧光基团(Opal 620、650、690、520、540、570,Akoya)染色10分钟,TBST冲洗3×2min;(9)若孵育多种抗体,则重复4-8步骤,进行染色。若只染一种,则在封片前重复步骤4,修复后冷却至室温,TBST冲洗后用双蒸水冲洗;(10)荧光染料DAPI染色封片。
结果如图2所示:多光谱免疫荧光技术标记196例肠癌组织芯片,蓝色标记DAPI,红色标记SLAFMF6,绿色标记角蛋白CK,紫色标记CD8A。通过对结果图进行评分,分析得在肠癌组织芯片中SLAMF6的表达与CD8+T细胞浸润程度成正相关(R=0.2177,p=0.0022)(图3-4D)。
实施例3:慢病毒转染SLAMF6过表达载载体构建稳转株。
具体步骤如下:(1)MC38细胞接种至六孔板,铺板的密度最好低于50%,当细胞生长状态良好且达到70%左右可以转染慢病毒SLAMF6过表达载体(LV-SLAMF6);(3)感染:将SLAMF6过表达载体的慢病毒(重组插入序GGCTGTTCCAATCGCTCCTGTTTGTCTTCTGCTTTGGCCCAGGGAATGTA)用DMEM完全培养基将病毒滴度最终稀释为1×108Tu/mL(公式:1mL培养基=920μL完全培养基+40μL助染液HitrtansG A/P+40μL的SLAMF6过表达载体的慢病毒);(4)使用终浓度为2ng/ml(4μL嘌呤霉素原液+2mL的完全培养基)的嘌呤霉素杀死没有转染慢病毒成功的MC38细胞,只保留转染成功的MC38细胞;(5)37℃培养16-24h后更换培养基,转染之后48-96h看荧光效率进行后续实验(绿色亮多代表转染效率高,不过实际上以RT-qPCR和Western blot的检测效率为主)。
结果如图3所示:构建空载体(LV-NC)及SLAMF6过表达载体(LV-SLAMF6)转染至MC38细胞,72h左右观察荧光效率(图3-A),接着通过RT-qPCR和Western blot技术证明SLAMF6的过表达载体可显著提高MC38细胞中SLAMF6 mRNA和蛋白的表达(图3-B、C)。
实施例4:过表达SLAMF6可增强对T细胞的招募作用。
T细胞迁移试验及活力测定(Transwell法)具体步骤如下:(1)将实验所需耗材试剂(24孔板、Transwell小室等)提前放入超净台中紫外灭菌30min;(2)镜下观察24孔板中细胞生长状态和生长密度,当生长状态良好且达到50%-60%时,将培养基更换为2%血清的完全培养基;(3)使用DMEM基础培养基将生长良好的Jurkat细胞进行重悬,吹打混匀并计数5×105/ml密度的Jurkat细胞重悬于500μL的DMEM基础培养基到Transwell上室中,下室添加650μL含2%血清的完全培养基;(4)下室接种慢病毒转染SLAMF6过表达载体的肠癌细胞或者使用可溶性的SLAMF6胞外域seSLAMF6按照浓度梯度去刺激肠癌细胞(0μg/mL、15μg/mL、30μg/mL);(5)培养箱共培养2h后,检测Transwell下室上清液中迁移的Jurkat细胞的数量和活力。
结果如图4所示:通过Transwell法来探究肠癌细胞中过表达SLAMF6对T细胞的招募作用,选取了Jurkat细胞作为T细胞的模型(图4-A),结果表明过表达SLAMF6可显著促进Jurkat细胞的迁移,减少了Jurkat细胞的凋亡(图4-B、C),并且CCK-8试验表明过表达SLAMF6能够显著抑制MC38细胞的增殖(图4-D)。
实施例5:过表达SLAMF6联合抗PD-L1对小鼠体内肿瘤的抑制作用。
具体步骤如下:构建小鼠结肠癌的异种移植瘤模型:(1)购买5周龄的雌性的C57BL/6鼠(免疫活性小鼠)于南通大学实验动物中心的SPF级屏障中按标准条件饲养,可自由获得食物和无菌水,笼子和窝料每3天更换一次,光照12h明暗交替;(2)小鼠使用的麻醉剂为吸入式麻醉剂异氟烷(吸入1.5-3.0%的异氟烷,在7-10分钟内即可达到麻醉效果),注射部位碘伏消毒,酒精脱碘;(3)用200μL的DMEM的基础培养基重悬5×106个小鼠结肠癌细胞MC38制成单细胞悬液,注射到小鼠右前肢的皮下部位;(4)接种一周后,用游标卡尺每三天测量一次长、宽、高,按椭球体体积的计算公式:V=π/6×长×宽×高,当肿瘤体积达到200mm3时开始进行药物治疗;(5)给药方式及剂量:对照组腹腔注射200μL的PBS,实验组腹腔注射抗PD-L1抗体(剂量12.5mg/kg)(6)观察20天后,小鼠用二氧化碳窒息法进行安乐死,轻轻取出皮下肿瘤,之后使用游标卡尺和电子天平测量肿瘤的体积和重量。
结果如图5所示:过表达SLAMF6联合抗PD-L1可显著抑制肠癌细胞的增殖。
实施例6:流式细胞术检测小鼠肿瘤组织中CD8+T细胞的浸润情况
具体步骤如下:(1)使用无菌的剪刀将小鼠肿瘤组织剪碎(重量:20~30g),转移至装有酶解液(肿瘤组织分离试剂盒)的无菌C管中;(2)机器设定小鼠肿瘤酶解的程序,一次37s,可设置多次,接着在37℃摇晃C管40min;(3)先用完全培养基浸润70μm的过滤网,将组织悬液过滤至15mL的离心管中,配平补齐8-10ml的完全培养基,300r/min,室温离心7min;(4)弃上清,加1mL的PBS重悬细胞,加3倍体积的红细胞裂解液裂解红细胞,冰上孵育5min;(5)补齐PBS至10mL终止反应;(6)2000r/min,室温离心5min,得到纯化的细胞,细胞数量要求1×106-1×107;(7)将细胞悬液离心后,弃上清,加100μL含10%胎牛血清的PBS,轻轻吹打混匀重悬细胞;(8)避光加入流式抗体,冰上孵育30min,每隔15min轻轻摇晃一次,保证抗体的充分孵育;(9)加入1mL的PBS洗涤细胞,1000r/min离心4min;(10)弃上清,再次加入1mL的PBS洗涤,1000r/min离心4min;(11)弃上清,加100μL的PBS重悬细胞转移至流式细胞仪,最后使用FlowJo分析结果。
结果如图6所示:取小鼠肿瘤组织进行流式细胞术,发现联合治疗组CD8+T细胞浸润最多。
以上所述仅为本发明创造的较佳实施例而已,并不用以限制本发明创造,凡在本发明创造的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明创造的保护范围之内。
Claims (9)
1.SLAMF6在制备用于具有以下一个以上功能的药物中的应用;
1)促进Jurkat细胞迁移,
2)减少Jurkat细胞凋亡,
3)抑制MC38细胞增殖,
4)增敏PD-L1抗体治疗效果,
5)增强CD8+T细胞对结直肠癌的杀伤活性。
2.SLAMF6慢病毒稳转细胞株的构建方法,其特征在于,包括:
1)构建慢病毒SLAMF6过表达载体;
2)将构建的慢病毒SLAMF6过表达载体转化到MC38细胞中;
3)培育筛选得到SLAMF6表达量显著提高的细胞株,即为SLAMF6慢病毒稳转细胞株。
3.根据权利要求2所述SLAMF6慢病毒稳转细胞株的构建方法,其特征在于,所述慢病毒SLAMF6过表达载体为LV-SLAMF6。
4.根据权利要求2所述SLAMF6慢病毒稳转细胞株的构建方法,其特征在于,所述慢病毒表达载体LV-SLAMF6的重组插入序列为ATGTTGTGGCTGTTCCAATCGCTCCTGTTTGTCTTCTGCTTTGGCCCAGGG AATGTA。
5.权利要求4所述SLAMF6慢病毒稳转细胞株的构建方法构建得到的慢病毒表达载体LV-SLAMF6。
6.权利要求5所述慢病毒表达载体LV-SLAMF6在促进Jurkat细胞迁移、减少Jurkat细胞凋亡中的应用。
7.权利要求5所述慢病毒表达载体LV-SLAMF6在抑制MC38细胞增殖中的应用。
8.权利要求5所述慢病毒表达载体LV-SLAMF6在增强CD8+T细胞对结直肠癌的杀伤活性中的应用。
9.权利要求5所述慢病毒表达载体LV-SLAMF6在增敏PD-L1抗体治疗效果中的应用。
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