CN110895280B - 用于预测鼻咽癌转移的免疫评分及其应用 - Google Patents

用于预测鼻咽癌转移的免疫评分及其应用 Download PDF

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CN110895280B
CN110895280B CN201911219504.1A CN201911219504A CN110895280B CN 110895280 B CN110895280 B CN 110895280B CN 201911219504 A CN201911219504 A CN 201911219504A CN 110895280 B CN110895280 B CN 110895280B
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麦海强
唐林泉
刘赛兰
焦磊
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Sun Yat Sen University Cancer Center
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Abstract

本发明提供了一组用于预测鼻咽癌转移风险的标志物，所述标志物包括：PDL1、CD163、CXCR5、CD117。本发明4个免疫分子表达构成的分子标签，可以反映鼻咽癌患者的生物学特异性，可以更准确地预测鼻咽癌患者的转移风险及预后，更好地指导临床用药，对无远处生存的预测效能要优于传统N分期。

Description

用于预测鼻咽癌转移的免疫评分及其应用
技术领域
本发明涉及生物医学领域，具体涉及一组预测鼻咽癌转移风险的标志物以及利用标志物建立预测鼻咽癌转移的免疫评分模型。
背景技术
鼻咽癌(NPC)是我国最常见的恶性肿瘤之一，以华南地区及香港地区发病率最高，年龄标化发病率可达20/10万以上。鼻咽癌好发年龄在40-50岁的壮年时期，容易对社会、经济、劳动力及家庭造成重大冲击。随着放疗技术的进步，鼻咽癌的局控率得到了明显提高，远处转移是目前鼻咽癌治疗失败的主要原因。
临床上主要是根据解剖学分期(TNM，T是原发灶，N是淋巴结，M是远处转移)来预测鼻咽癌远处转移。但TNM分期仅反映了肿瘤的解剖范围。由于肿瘤的异质性，同一分期的患者预后差异较大，所以仅依靠临床分期并不能准确区分患者的转移风险。所以需要更精确的辅助预测预后模型来指导患者的个体化治疗。
新发现的证据表明，特定的肿瘤微环境可促进肿瘤进展，其特征的多样性可用于多种癌症的分子分类和预后预测。既往研究表明，巨噬细胞、肥大细胞和中性粒细胞浸润的增加可对鼻咽癌产生不良的预后影响。此外，许多研究报道淋巴细胞浸润与鼻咽癌良好的预后相关。然而，这些淋巴细胞的抗肿瘤反应往往受到免疫检测点的抑制。PD-1、TIM-3是著名的免疫检查点，其分别主要通过连接PD-L1和Galectin-9来阻碍T细胞活化。此外，LAG-3和Galectin-1是近年来备受关注的新型肿瘤免疫治疗靶点。以往对鼻咽癌肿瘤微环境的研究样本量小，缺乏独立的验证，且主要关注的标记物数量有限。此外，标记物的共同表达和非恶性细胞的特征往往被忽视。由于肿瘤细胞和基质细胞协调促进肿瘤的进展和转移，因此有必要根据它们的相对位置对肿瘤微环境的整体情况进行描述。此外，不同临床结局的患者，尤其是远处转移患者的免疫模式的差异也值得关注和强调。
发明内容
本发明利用荧光多重免疫组化通过对大样本鼻咽癌组织芯片进行17种免疫细胞和免疫检查点染色，包括6个重要免疫检测点分子(PD-1，PD-L1，TIM-3，Galectin-9，LAG-3，Galentin-1)和11个预后相关免疫细胞：成熟T淋巴细胞(CD3)，辅助T细胞(CD4)，细胞毒性T细胞(CD8)，中性粒细胞(CD66b)，滤泡辅助T细胞(CXCR5)，调节性T细胞(Foxp3)，单核细胞(CD68)，M2巨噬细胞(CD163)，1型辅助T细胞(T-bet)和肥大细胞(CD117)，旨在建立对鼻咽癌具有潜在预后价值的免疫评分模型并进行验证。
本发明的目的在于提供一组可以有效预测鼻咽癌转移风险的标志物。
本发明的另一个目的在于该组标志物在制备测鼻咽癌预后试剂中的应用。
本发明所采取的技术方案是：一组用于预测鼻咽癌转移风险的标志物，该组标志物包括：PDL1、CD163、CXCR5、CD117。
进一步地，所述的用于预测鼻咽癌转移风险的标志物在用于预测鼻咽癌风险免疫评分公式中的应用。
进一步地，所述用于鼻咽癌风险预测的免疫评分公式为：＝(0.013479×1000×PDL1阳性且CD163阳性细胞占瘤内所有细胞的百分比)+(0.057512×CXCR5的H-score)+(0.011048×CD117的H-score)，该公式中百分比及H-score均没有单位，其中H-score＝∑[(I+I)×PC]，I和PC分别代表染色强度以及在每个强度染色细胞的百分数。
进一步地，所述的用于预测鼻咽癌转移风险的标志物在制备用于预测鼻咽癌风险试剂盒中的应用。
本发明的有益效果：本发明4个免疫分子表达构成的分子标签，可以反映鼻咽癌患者的生物学特异性，可以更准确地预测鼻咽癌患者的转移风险及预后，更好地指导临床用药，对无远处生存的预测效能要优于传统N分期。
附图说明
图1：研究流程图；
图2：染色流程图；
图3：在194例训练组患者中利用LASSO从8个指标中筛选出跟转移预后最相关的免疫预后指标(PD-L1+CD163+，CD117，CXCR5)；
图4：K-M生存分析显示训练组(n＝194)和验证组(n＝304)中免疫评分高风险组鼻咽癌患者无远处转移生存(A、C)和无进展生存均较差(B、D)；
图5：K-M生存分析显示训练组与验证组中免疫评分低风险组鼻咽癌患者是否接受诱导+同期放化疗的无远处转移生存(A)和无进展生存(B)，n＝303；免疫评分高风险组鼻咽癌患者是否接受诱导+同期放化疗的无远处转移生存(C)和无进展生存(D)，n＝85；
图6：预测局部晚期鼻咽癌无远处转移生存的线列图。
具体实施方式
为了更加简洁明了的展示本发明的技术方案、目的和优点，下面结合实验及其附图对本发明做进一步的详细描述。
1、病例筛选：
发明人选取了498例经过根治性放疗的初治非转移的鼻咽癌患者样本(训练组，n＝194；验证组，n＝304)，其中有37.6％(187/498)的患者接受了顺铂为基础的同期疗，40.4％(201/498)患者接受了诱导加同时期放化疗。中位随访时间为62.0个月(四分位数IQR 26.1～60.2)，498例患者中62例(12.4％)在随访期间发生远处转移。对这498例患者的初诊活检石蜡组织标本制作成组织芯片，每个患者都保证有一个包含70％以上的瘤内芯点，如果可能的话再额外打一个包含70％以上的间质芯点。
通过荧光多重免疫组化和智能组织定量软件(PerkinElmer inFormTM)分析：发明人首先采用荧光多重免疫组化检测了训练组中25例高转移风险(初诊无转移，但根治性放疗后3年出现远处转移)和29例低转移风险(初诊无转移，且根治性治疗后随访5年未出现转移)鼻咽癌患者的瘤内和间质的组织芯片中的17个免疫指标的表达，具体染色流程如图2所示。利用新型的专业定量病理分析软件(PerkinElmer inFormTM)可以将智能组织识别算法与光谱解读和多标记分析融为一体。软件通过对不同蛋白在特定细胞、特定部位上的表达强度进行定量测定，给出免疫组织化学评分结果，或者是共定位表达的比例。一位鼻咽癌患者可同时获得瘤内和间质细胞的17个免疫指标的两套数据进行单因素生存分析。通过初步筛选得到8个与鼻咽癌转移预后相关的免疫分子：CD8，TIM-3，PD-L1，CD163，CXCR5，Foxp3，CD117，LAG-3。
2、鼻咽癌转移免疫分子靶标的发现：
发明人利用荧光多重免疫组化和自动定量技术在训练组194例组织芯片中检测这8个免疫分子的表达及共表达，利用LASSO筛选出与无远处转移生存最为相关的免疫分子构建模型(见图3)，发明人将该模型命名为免疫评分公式。其计算公式为：
免疫评分公式＝(0.013479×1000×PDL1阳性且CD163阳性细胞占瘤内所有细胞的百分比)+(0.057512×CXCR的H-score)+(0.011048×CD117的H-score)，该公式中百分比及H-score均没有单位，H-score＝∑[(I+I)×PC]，I和PC分别代表染色强度以及在每个强度染色细胞的百分数。
用X-tile软件生成阈值为0.8，由上述免疫评分公式将训练组194例中的152例(78.4％)患者分为高风险组，42例(21.6％)分为低风险组。由图4A所示，这两组患者的5年无远处转移率在高风险组为61.4％(95％CI 45.9-76.9)，在低风险组为89.1％(82.2-96.0)；由图4B所示，这两组患者的5年无进展生存率在高风险组为54.0％(35.2-72.8)，在低风险组为89.1％(82.2-96.0)。低风险组的5年无远处转移率和5年无进展生存率明显高于高风险组。
3、转移靶标的进一步验证
发明人随后在外院样本中对这一免疫评分公式以及公式中使用的标志物进行了验证。
在外院验证的304例患者中，本发明的免疫评分公式其中将70例(23.0％)患者分为高风险组，234例(77.0％)分为低风险组。结果如图4C、D所示，与低风险组患者相比，高风险患者的无远处转移生存(HR 3.502，95％CI 1.791-6.847；p＜0.0001)，无进展生存(HR1.964，95％CI 1.165-3.309；p＝0.011)均较差。
此外，发明人还分析了本发明免疫评分是否能预测鼻咽癌患者对诱导联合同时期放化疗的获益。在本院与外院的498例患者中，有37.6％(187/498)的患者接受了顺铂为基础的同期放化疗，40.4％(201/498)患者接受了诱导加同时期放化疗，发现低风险组的患者接受诱导加同期放化疗后无远处转移(HR 0.355，95％CI 0.147-0.857；p＝0.021)及无进展生存(HR 0.590，95％CI 0.351-0.992；p＝0.047)得到显著改善，而高风险组无统计学差异(DMFS：HR 1.294，0.553-3.029；p＝0.552；PFS：HR 1.248，0.590-2.639；p＝0.563)(见图5)。
4、提高预测鼻咽癌转移风险的准确性，
发明人将免疫评分及其他独立预后因素纳入列线图分析，这些预测因素包括：免疫评分、N分期、HGB水平和免疫评分的C-index值为0.703。在这些因素中有着最高预测效能。根据5年DMFS(无远处转移生存率)预测值结果绘制的预测曲线在两组患者均显示很高的一致性，训练组(C-index：0.791，95％CI 0.720-0.862)，验证组(C-index；0.729，95％CI0.630-0.828)(见图6)。
5、对比效果
相对于既往的用于预测鼻咽癌转移风险的标志物而言，本发明采用的标志物与肿瘤免疫微环境密切相关，可以反映患者的免疫状况。此外，本发明的标志物是根据它们的在肿瘤微环境中的相对位置对肿瘤微环境进行客观描述，更准确更可靠，最后建立并验证了该对鼻咽癌具有潜在预后价值的免疫评分模型。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (3)

1.一组用于预测鼻咽癌转移风险的标志物，其特征在于，所述标志物由PDL1、CD163、CXCR5和CD117组成。
2.如权利要求1所述的用于预测鼻咽癌转移风险的标志物，其特征在于，所述标志物用于预测鼻咽癌转移风险的免疫评分公式根据LASSO模型确定；所述免疫评分公式为：＝(0.013479×1000×PDL1阳性且CD163阳性细胞占瘤内所有细胞的百分比)+(0.057512×CXCR5的H-score)+(0.011048×CD117的H-score)，该公式中百分比及H-score均没有单位，其中H-score＝∑[(I+I)╳PC]，I和PC分别代表染色强度以及在每个强度染色细胞的百分数。
3.如权利要求1所述的用于预测鼻咽癌转移风险的标志物在制备用于预测鼻咽癌转移风险的试剂盒中的应用。
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