CN114622023A - 一种预测肿瘤化疗联合免疫治疗疗效的标志物及其应用 - Google Patents
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Abstract
本发明公开了一种预测肿瘤化疗联合免疫治疗疗效的标志物及其应用，属于生物医药技术领域，所述标志物为选自肿瘤组织内部的链球菌属、梭杆菌属、消化链球菌属、微单胞菌属、卡氏菌属中的至少一种微生物；利用16sRNA检测患者肿瘤组织相应微生物表达情况，之后对相应数据，进行主坐标分析及AUC预测效价计算，得到具有预测食管癌患者化疗联合免疫治疗疗效的微生物种类，相较于目前所报道的可以用于预测免疫治疗预后的工具，如PD1,PD‑L1,肿瘤突变复合（TMB）等，本申请具有准确性更高、快捷方便、价格更低等优势。
Description
技术领域
本发明涉及生物医药技术领域，尤其涉及一种以微生物作为标志物的预测肿瘤化疗联合免疫治疗疗效的试剂盒及其应用。
背景技术
食管癌是世界范围内常见的死亡相关的癌症之一，其死亡率在癌症中排第六位。手术是治疗食管癌的首选方法。早期食管癌可以直接手术切除，而对于部分无法直接进行手术切除的患者，可以先进行以化疗为基础联合免疫治疗的的方法进行治疗，在缩小瘤体后使患者获得手术机会。然而，不同患者接受治疗的效果有较大差异，目前尚无可以有效预测食管癌患者接收化疗联合免疫治疗疗效的工具。因此，寻找有效的方案来预测化疗联合免疫治疗的疗效，可为患者提供有效的预测手段，为临床制定诊疗计划提供指导，是本领域亟需解决的问题。
发明内容
本发明的目的之一，就在于提供一种预测肿瘤化疗联合免疫治疗疗效的标志物，以解决上述问题。
为了实现上述目的，本发明采用的技术方案是这样的：一种预测肿瘤化疗联合免疫治疗疗效的标志物，所述标志物为选自链球菌属、梭杆菌属、消化链球菌属、微单胞菌属、卡氏菌属中的至少一种微生物。
所述标志物为肿瘤组织内部检测到的具有预测肿瘤化疗联合免疫治疗疗效的微生物。
本申请的发明人经过大量试验研究，基于16sRNA检测分析发现：免疫治疗联合化疗有效和无效患者的肿瘤组织中，链球菌属（Streptococcus）、梭杆菌属（Fusobacterium）、消化链球菌属（Peptostreptococcus）、微单胞菌属（Parvimonas）、卡氏菌属（CatonellaMoore and Moore）的微生物组成存在显著差异。其中，链球菌属的数量与食管癌免疫治疗的疗效正相关；而梭杆菌属，微单胞菌属，消化链球菌属，链球菌属的数量均与免疫治疗的疗效呈负相关，因此，通过含有上述微生物的检测试剂盒对肿瘤组织进行微生物定量和定性检测，可以预测肿瘤免疫治疗的疗效。
本发明的目的之二，在于提供一种上述的标志物在预测肿瘤化疗联合免疫治疗疗效中的应用。
作为优选的技术方案：所述肿瘤为食管癌。
作为优选的技术方案：预测标准为：所述链球菌属与CD8+T细胞浸润呈正相关，与CD4+及FOXP3+T细胞浸润呈负相关；所述梭杆菌属、消化链球菌属、微单胞菌属和卡氏菌属与CD8+T细胞浸润呈负相关，与CD4+及FOXP3+T细胞浸润呈正相关。
通过发明人进一步分析，发现上述5种微生物与患者肿瘤组织内部免疫细胞的浸润呈现上述明显的相关性，ROC曲线分析其AUC值均高于85%。
通过数字化PCR检测肿瘤组织内部上述5种微生物的含量。5种微生物的特异性引物如下：
与现有技术相比，本发明的优点在于：利用16sRNA检测患者肿瘤组织内部相应微生物表达情况，之后通过分析相应数据判断该食管癌患者化疗联合免疫治疗疗效，相较于目前所报道的可以用于预测免疫治疗预后的工具，如PD1,PD-L1,肿瘤突变复合（TMB）等，本申请具有所需组织样本量小，检测速度快，准确性更高、价格更低等优势。
附图说明
图1为食管癌组织与癌旁组织切片的微生物荧光原位杂交（FISH）图与免疫组化图分别显示革兰氏阳性菌（LTA）及革兰氏阴性菌（LPS）的表达情况；
图2为食管癌组织与癌旁组织内部微生物的组成类别图；
图3为接受免疫治疗的食管癌患者，有应答组与无应答组的微生物类型分析图；
图4为门水平分析了有应答组和无应答组微生物的构成情况；
图5为接受化疗联合免疫治疗的治疗食管癌患者，其肿瘤组织内部微生物的组成图；
图6肿瘤组织内部微生物与CD4、CD8、FOXP3免疫细胞浸润的相关性分析图；
图7为几种不同微生物用于预测治疗效果的ROC曲线图。
具体实施方式
下面将结合附图对本发明作进一步说明。
实施例1：食管癌癌旁及肿瘤组织中存在大量微生物
采用无菌冻存管收集手术切除食管癌标本，并在无菌条件下保存。使用时制备固定后冰冻切片，采用RNAscope 16sRNA探针，在HybEZ ™杂交炉中采用RNAscope® 1X靶标修复试剂对食管癌癌旁组织和肿瘤组织中的微生物进行探测。同时，采用免疫组织化学染色，对相同部位的组织进行LPS与LTA的染色，结果如图1所示，食管癌癌旁组织和肿瘤组织中有大量微生物16sRNA的存在，以及LPS和LTA的表达。对食管癌癌旁组织和肿瘤组织进行微生物16sRNA的测定，结果如图2所示：
从图2可以看出，食管癌肿瘤组织和癌旁组织中都存在大量微生物。
对肿瘤组织和癌旁组织中的微生物进行β多样性分析，PCoA通过样本间距离矩阵的一个旋转，不改变样本点之间的相互位置的主坐标分析结果表明，二者内部的微生物存在明显的差异；进一步对采取化疗联合免疫治疗的食管癌患者肿瘤组织中的微生物进行PCoA分析，结果表明对治疗有反应和无反应患者肿瘤组织内部微生物存在显著差异，如图3所示，
实施例2：对治疗有反应或无反应患者组织内部微生物有明显差异
食管癌患者肿瘤组织中的微生物的16sRNA结果表明，图4在门水平分析了有应答组和无应答组微生物的构成情况，对治疗有应答的患者和无应答的患者相比，肿瘤组织内部微生物存在显著差异，如图3所示；图5从更细微的属水平分析发现，有反应及无反应组，链球菌属、梭菌属、消化链球菌属、微单胞菌属、卡氏菌属等为具有显著差异的微生物。
上述数据可以证明，对治疗有反应或无反应患者肿瘤组织内部微生物有明显差异。
实施例3：多种微生物具有预测患者治疗疗效的作用
上述数据已经得出，免疫联合化疗应答组和无应答组中差异的微生物与T细胞的富集有关，从而与免疫联合化疗的效果建立了关系。再进一步通过Pearson相关性分析具有疗效预测价值的五种菌（属水平）与免疫联合化疗治疗疗效的相关性，如图6所示，结果表明，链球菌属与CD8+T细胞浸润呈正相关，与CD4+T、FOXP3+T细胞浸润呈负相关，而梭菌属、消化链球菌属、微单胞菌属、卡氏菌属则与CD8+T细胞浸润呈负相关，与CD4+T、FOXP3+T细胞浸润呈正相关；
然后分别以各种微生物的含量为截取值，分析上述微生物预测治疗疗效的敏感性和特异性，作ROC曲线，结果如图7所示，从图中可以得知，所选五种微生物的AUC值均大于0.85。
综上所述，本发明的五种肿瘤组织内微生物具有预测患者化疗联合免疫治疗疗效的作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (6)
1.一种预测肿瘤化疗联合免疫治疗疗效的标志物，其特征在于：所述标志物为选自肿瘤组织内部的链球菌属、梭杆菌属、消化链球菌属、微单胞菌属、卡氏菌属中的至少一种微生物。
2.根据权利要求1所述的标志物，其特征在于：所述标志物为肿瘤组织内部检测到的具有预测肿瘤化疗联合免疫治疗疗效的微生物。
3.权利要求1所述的标志物的应用。
4.根据权利要求3所述的应用，其特征在于：所述肿瘤为食管癌。
5.根据权利要求3所述的应用，其特征在于，预测标准为：所述链球菌属与CD8+T细胞浸润呈正相关，与CD4+及FOXP3+T细胞浸润呈负相关；所述梭杆菌属、消化链球菌属、微单胞菌属和卡氏菌属与CD8+T细胞浸润呈负相关，与CD4+及FOXP3+T细胞浸润呈正相关。
6.根据权利要求3所述的应用，其特征在于：所述链球菌属、梭杆菌属、消化链球菌属、微单胞菌属和卡氏菌属在化疗联合免疫治疗疗效的预测敏感性和特异性，AUC值均大于0.85。
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| CN117074679B (zh) * | 2023-09-20 | 2024-06-11 | 上海爱谱蒂康生物科技有限公司 | 生物标志物组合及其在预测免疫治疗联合化疗治疗食管癌效果中的应用 |
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