WO2021147643A1 - Cxcl13检测剂在制备预测免疫治疗效果的试剂盒中的用途 - Google Patents

Cxcl13检测剂在制备预测免疫治疗效果的试剂盒中的用途 Download PDF

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WO2021147643A1
WO2021147643A1 PCT/CN2020/142063 CN2020142063W WO2021147643A1 WO 2021147643 A1 WO2021147643 A1 WO 2021147643A1 CN 2020142063 W CN2020142063 W CN 2020142063W WO 2021147643 A1 WO2021147643 A1 WO 2021147643A1
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cxcl13
tumor
cells
immunotherapy
specific
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周鹏辉
刘振江
何晶晶
熊昕昕
俞快
董兴骏
李硕
付凌怡
廖双叶
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中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所）
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  • the invention belongs to the field of medicine, and specifically relates to the use of a CXCL13 detection agent in preparing a kit for predicting the effect of immunotherapy.
  • Immunotherapy is a new and effective tumor treatment method.
  • Immune checkpoint inhibitors represented by the PD-1/PD-L1 antibody have achieved significant therapeutic effects in multiple clinical trials and have been approved for multiple indications.
  • immunotherapy only shows good curative effect in some patients. How to accurately find these effective patients is a difficult problem in current clinical treatment.
  • Another method is to evaluate tumor mutational burden by second-generation sequencing of tumor tissue.
  • tumor antigens need to be delivered to anti-tumor T cells through antigen-presenting cells to activate these T cells to attack and kill tumors.
  • obstacles in the process of tumor antigen delivery such as the loss of histocompatibility antigen molecules, it will cause the anti-tumor immune response to fail to activate, and immunotherapy will promptly have higher tumor mutations for such patients with ineffective tumor antigens.
  • the load is also ineffective.
  • Tumor-specific T cells directly attack and kill tumor cells through specific recognition of tumor antigens, and play the most critical role in the anti-tumor immune response.
  • the above two detection methods both indirectly assess the strength of the anti-tumor immune response formed by tumor-specific T cells, thereby predicting the effect of immunotherapy. Because it is an indirect indicator, the forecast accuracy is low. Therefore, if the number of tumor-specific T cells in the tumor can be directly assessed, it will be able to more accurately predict the effect of immunotherapy, and thereby screen the benefiting population of the treatment.
  • the purpose of the present invention is to provide a technical solution that can effectively and accurately predict the effect of immunotherapy in view of the above technical problems to be solved.
  • the present invention provides a use of a CXCL13 detection agent in preparing a kit for predicting the effect of immunotherapy.
  • the CXCL13 detection agent referred to in the present invention refers to a preparation capable of detecting the expression level of CXCL13 in cells, including but not limited to known commercial CXCL13 detection preparations, especially for detecting the expression level of CXCL13 by immunohistochemical staining Preparations.
  • the CXCL13 detection agent is used to detect the expression level of CXCL13 in tumor-specific T cells.
  • the tumor-specific T cells are CD4 tumor-specific T cells or CD8 tumor-specific T cells.
  • the present invention also provides the use of the CXCL13 detection agent in preparing a kit for predicting the effect of immunotherapy by detecting the expression level of CXCL13 in tumor-specific T cells.
  • the present invention also provides a kit for predicting the effect of immunotherapy, which includes a CXCL13 detection agent for detecting the expression level of CXCL13 in tumor-specific T cells.
  • the present invention also provides a method for predicting the effect of immunotherapy by detecting the expression level of CXCL13 in tumor-specific T cells to predict the effect of immunotherapy.
  • the tumor-specific T cells are CD4 tumor-specific T cells or CD8 tumor-specific T cells.
  • the immunotherapy includes but is not limited to PD-1 antibody therapy.
  • the tumor means a new organism formed by the proliferation of local tissue cells under the action of various tumor-causing factors, including but not limited to melanoma, lung cancer, non-small cell lung cancer, kidney cancer, lymphoma, head and neck squamous cells Cancer, bladder cancer, colorectal cancer, liver cancer, stomach cancer, prostate cancer, osteosarcoma, especially melanoma.
  • various tumor-causing factors including but not limited to melanoma, lung cancer, non-small cell lung cancer, kidney cancer, lymphoma, head and neck squamous cells Cancer, bladder cancer, colorectal cancer, liver cancer, stomach cancer, prostate cancer, osteosarcoma, especially melanoma.
  • the experimental results show that the CXCL13 detection agent of the present invention can effectively and accurately detect the expression level of CXCL13, and the expression level can be used to screen patients with effective immunotherapy.
  • the expression level of CXCL13 is positively correlated with the patient's response to immunotherapy, that is, the higher the expression level of CXCL13, the better the immunotherapy effect; the lower the expression level of CXCL13, the worse the immunotherapy effect.
  • Figure 1 shows the specific expression of CXCL13 in tumor-specific T cells.
  • Figure 2 shows the expression level of CXCL13 in tumor tissues detected by immunohistochemistry.
  • Figure 3 shows the correlation between the expression level of PD-L1 and the patient's response to immunotherapy.
  • Figure 4 shows the correlation between the expression level of PD-L1 and the patient's progression-free survival.
  • Figure 5 shows the correlation between the expression level of CXCL13 and the patient's response to immunotherapy.
  • Figure 6 shows the correlation between the expression level of CXCL13 and the patient's progression-free survival.
  • this program found the molecular marker CXCL13 specifically expressed in tumor-specific T cells by analyzing the gene expression characteristics of tumor-specific T cells, and established a method for screening patients with effective immunotherapy by detecting the expression level of CXCL13 .
  • the tumor tissues and normal tissues of lung cancer patients are processed into single cell suspension, and the blood is rationally removed by Ficoll gradient to remove red blood cells to obtain monocytes. Then, CD3 antibody staining was performed, and CD3 positive cells were sorted out by flow cytometry. Finally, single-cell sequencing was performed using the 5'single-cell RNAseq kit of 10x genomics to obtain the transcriptome and TCR sequence of a single cell. Then the T cells that have expanded in tumor tissues are selected. Among them, T cells that have expanded only in tumor tissues are defined as tumor-specific T cells, and they are also in normal tissues or blood.
  • Expanded T cells are defined as tissue resident cells (Tissue resident T cells), and CD4 T cells that express FOXP3 in tumor tissues are defined as regulatory T cells (Regulatory T cells).
  • tissue resident T cells Tissue resident T cells
  • regulatory T cells regulatory T cells
  • Immunohistochemical staining of paraffin tumor tissue sections of melanoma patients with CXCL13 antibody can clearly detect the expression of CXCL13 protein. As shown in Figure 1, the left picture shows the high expression of CXCL13, and the right picture shows the low expression of CXCL13.
  • Baked slices slice the paraffin tumor tissues of melanoma patients into slices in a 60 °C oven and bake slices for 1.5 hours.
  • Eliminate endogenous peroxidase move the slices into a humid box, add freshly prepared 3% v/v hydrogen peroxide, incubate at room temperature for 10 minutes, rinse with PBS 3 times, 3 minutes each time.
  • Blocking absorb the PBS with absorbent paper, add normal goat serum blocking solution dropwise on the slide, and block for 30 minutes at room temperature.
  • Secondary antibody incubation take out the slices, rinse with PBS 3 times, 3 minutes each time. Place the slices in a humid box, add the secondary antibody working solution dropwise, incubate at room temperature for 1 hour, and rinse with PBS 3 times, each for 3 minutes.
  • Color development Add DAB color development solution dropwise on the slices, and observe the degree of color development under a microscope. The color development is 5-10 minutes, and the PBS rinses for 1 minute.
  • Eliminate endogenous peroxidase move the slices into a humid box, add freshly prepared 3% v/v hydrogen peroxide, incubate at room temperature for 10 minutes, rinse with PBS 3 times, 3 minutes each time.
  • Blocking absorb the PBS with absorbent paper, add normal goat serum blocking solution dropwise on the slide, and block for 30 minutes at room temperature.
  • Secondary antibody incubation take out the slices, rinse with PBS 3 times, 3 minutes each time. Place the slices in a humid box, add the secondary antibody working solution dropwise, incubate at room temperature for 1 hour, and rinse with PBS 3 times, each for 3 minutes.
  • Color development Add DAB color development solution dropwise on the slices, and observe the degree of color development under a microscope. The color development is 5-10 minutes, and the PBS rinses for 1 minute.

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Abstract

一种CXCL13检测剂在制备预测免疫治疗效果的试剂盒中的用途，CXCL13检测剂是用于检测CXCL13在肿瘤特异T细胞中的表达水平的试剂。一种用于预测免疫治疗效果的试剂盒，其包括CXCL13检测剂。一种通过检测CXCL13在肿瘤特异T细胞中的表达水平来预测免疫治疗效果的方法，其中CXCL13检测剂能够有效、准确地检测CXCL13的表达水平，并通过该表达水平来预测免疫治疗效果。

Description

CXCL13检测剂在制备预测免疫治疗效果的试剂盒中的用途 技术领域
本发明属于医药领域，具体涉及CXCL13检测剂在制备预测免疫治疗效果的试剂盒中的用途。
背景技术
免疫治疗是一种全新的、有效的肿瘤治疗手段。以PD-1/PD-L1抗体为代表的免疫检查点抑制剂已经在多个临床试验中取得显著的治疗效果，并获批了多个适应症。然而，免疫治疗只在一部分患者中表现出较好的疗效，如何准确找到这部分有效的患者，是目前临床治疗的一个难题。
目前预测免疫检查点抑制剂的方法主要有两种。一种是通过免疫组化检测PD-L1蛋白在肿瘤中表达水平的高低来预测患者有效率。PD-L1的表达受效应T细胞分泌的INFG所调控，PD-L1高表达预示着肿瘤中有较多的效应T细胞，因此是一个间接反应抗肿瘤免疫反应的指标。然而，临床结果表明，PD-L1的高表达仅在一些肿瘤类型中与免疫治疗效果有一定的相关性，还有很多肿瘤类型是不相关的。而一部分PD-L1阴性的患者同样具有较好的治疗效果。这表明PD-L1无法准确预测免疫治疗的效果。同时，目前市场上存在多种品牌及型号的PD-L1抗体，其检测方法、染色强度及判读方式均不一致，对于是否用药、如何用药造成了较大的干扰。
另外一种方法是通过对肿瘤组织进行二代测序，评估肿瘤突变负荷。肿瘤突变越多，产生的肿瘤抗原越多，形成的抗肿瘤免疫反应则越强。因此肿瘤突变负荷是通过肿瘤抗原的多少来间接反应抗肿瘤免疫反应的强弱，从而预测免疫治疗效果。但是由于肿瘤抗原需要通过抗原呈递细胞传递给抗肿瘤T细胞，从而激活这些T细胞来攻击和杀伤肿瘤。但是如果在肿瘤抗原传递过程中出现障碍，如发生组织相容性抗原分子的丢失等，会导致抗肿瘤免疫反应无法激活，免疫治疗对这类无法有效肿瘤抗原的患者，及时具有较高肿瘤突变负荷，同样是无效的。
肿瘤特异T细胞通过对肿瘤抗原的特异识别，直接攻击和杀伤肿瘤细胞，在抗肿瘤免疫反应中具有最关键的作用。以上两种检测方法都是间接地评估肿瘤特异T细胞所形成的抗肿瘤免疫反应的强弱，从而预测免疫治疗效果。由于是间接指标，预测准确性较低。因此，如果能够直接评估肿瘤特异T细胞在肿瘤中的数量，将能够更准确地预测免疫治疗效果， 从而筛选出治疗的获益人群。然而，目前缺乏肿瘤特异T细胞的标志物，无法进行预测。
发明内容
本发明的目的是针对以上要解决的技术问题，提供一种能够有效、准确预测免疫治疗效果的技术方案。
为了实现以上目的，本发明提供了一种CXCL13检测剂在制备预测免疫治疗效果的试剂盒中的用途。
本发明所称的CXCL13检测剂是指能够检测到CXCL13在细胞中表达水平的制剂，包括但不限于已知的商业化的CXCL13检测制剂，特别是用于通过免疫组化染色来检测CXCL13表达水平的制剂。
优选地，所述CXCL13检测剂用于检测CXCL13在肿瘤特异T细胞中的表达水平。
优选地，所述肿瘤特异T细胞为CD4肿瘤特异T细胞或CD8肿瘤特异T细胞。
此外，本发明还提供了CXCL13检测剂在制备通过检测CXCL13在肿瘤特异T细胞中的表达水平来预测免疫治疗效果的试剂盒中的用途。
另一方面，本发明还提供了一种用于预测免疫治疗效果的试剂盒，其包括用于检测CXCL13在肿瘤特异T细胞中的表达水平的CXCL13检测剂。
另一方面，本发明还提供了一种预测免疫治疗效果的方法，该方法通过检测CXCL13在肿瘤特异T细胞中的表达水平来预测免疫治疗效果。
优选地，所述肿瘤特异T细胞为CD4肿瘤特异T细胞或CD8肿瘤特异T细胞。
优选地，所述免疫治疗包括但不限于PD-1抗体治疗。
优选地，所述肿瘤意指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物，包括但不限于黑色素瘤、肺癌、非小细胞肺癌、肾癌、淋巴瘤、头颈鳞癌、膀胱癌、结直肠癌、肝癌、胃癌、前列腺癌、骨肉瘤，特别是黑色素瘤。
实验结果表明，本发明的CXCL13检测剂能够有效、准确地检测CXCL13的表达水平，并通过该表达水平来筛选免疫治疗有效患者。CXCL13的表达水平与患者对免疫治疗的响应呈正相关，即，CXCL13表达水平越高，则免疫治疗效果越好；CXCL13表达水平越低，则免疫治疗效果越差。
附图说明
图1示出了CXCL13在肿瘤特异T细胞中的特异表达。
图2示出了免疫组化检测CXCL13在肿瘤组织中的表达水平。
图3示出了PD-L1表达水平与患者对免疫治疗反应的相关性。
图4示出了PD-L1表达水平与患者无进展生存期的相关性。
图5示出了CXCL13表达水平与患者对免疫治疗反应的相关性。
图6示出了CXCL13表达水平与患者无进展生存期的相关性。
具体实施方式
下面结合具体实施例和附图，对本发明的技术方案作进一步的详述，但本发明的保护范围并不限于以下实施例。
值得注意的是，出于简要清楚的目的，以下实施例中对一些常规的技术操作步骤、试剂、仪器并未进行细致的描述，但应理解，如未特别说明，这些常规技术操作步骤、试剂、仪器对本领域普通技术人员而言是显而易见的。
总体而言，通过对患者的肿瘤组织、正常组织和血液中的T细胞进行单细胞RNA测序，在肿瘤组织中找到了两群肿瘤特异T细胞，一群是CD4肿瘤特异T细胞，另一群是CD8肿瘤特异T细胞。将这两群细胞分别与肿瘤中的其他T细胞进行转录组比较，发现CXCL13在这两群肿瘤特异T细胞中都高表达(图1)，表明CXCL13是肿瘤特异T细胞的分子标志物。然后建立CXCL13的免疫组化染色方案(包括治疗前和治疗后)，通过对肿瘤组织切片的染色，实现对CXCL13表达水平的准确评估(图2)。
对患者治疗前的肿瘤组织切片进行染色，预测免疫治疗效果。与以往的报道相一致，PD-L1高表达只能够部分预测免疫治疗的疗效，无论是治疗效果还是患者的生存期(图3、图4)，与PD-L1低表达患者的差异都比较小。而通过CXCL13染色发现，高表达患者与低表达患者之间，具有非常显著的疗效差异(图5)。同时，CXCL13高表达的患者也具有明显的生存期优势(图6)，表明通过CXCL13预测免疫治疗疗效的方法在准确率方面明显优于通过PD-L1预测免疫治疗疗效的方法。
综合以上结果，本方案通过分析肿瘤特异T细胞的基因表达特点，找到了在肿瘤特异T细胞中特异表达的分子标志物CXCL13，并建立了通过检测CXCL13的表达水平来筛选免疫治疗有效患者的方法。
肺癌患者的肿瘤组织和正常组织被处理成单细胞悬液，血液则通过Ficoll梯度理性去除红细胞，获得单核细胞。然后进行CD3抗体染色，通过流式分选出CD3阳性细胞。最后通过10x genomics的5’单细胞RNAseq试剂盒进行单细胞测序，获得单个细胞的转录组和TCR 序列。然后将在肿瘤组织内发生了扩增的T细胞挑选出来，其中只在肿瘤组织中发生了扩增的T细胞定义为肿瘤特异T细胞(Tumor specific T cell)，而在正常组织或者血液中也发生了扩增的T细胞定义为组织驻留细胞(Tissue resident T cell)，在肿瘤组织中表达FOXP3的CD4T细胞定义为调节性T细胞(Regulatory T cell)。我们发现在CD8和CD4T细胞亚群中均存在肿瘤特异T细胞。通过对这些细胞的转录组进行比较发现，CXCL13在CD8和CD4肿瘤特异T细胞中都高表达，是肿瘤特异T细胞的特有的分子标志物。图1展示的是在各个细胞亚群中每个细胞的CXCL13表达水平。
实施例
通过CXCL13抗体对黑色素瘤患者的石蜡肿瘤组织切片进行免疫组化染色，能够清晰检测CXCL13蛋白的表达，如图1所示，左图为CXCL13高表达，右图为CXCL13低表达。
选取约60例接受了PD-1抗体治疗的黑色素瘤患者，分别取治疗前和治疗后的肿瘤切片，分别进行免疫组化染色检测CXCL13和PD-L1，分析其表达量与患者对抗体反应的相关性。
免疫组化染色检测CXCL13的具体步骤如下：
1.烤片：将黑色素瘤患者的石蜡肿瘤组织切片入放入60℃烤箱中烤片1.5h。
2.脱蜡：切片在二甲苯中放置10min，更换二甲苯，再放置10min。
3.水化：切片依次放入100％v/v乙醇、100％v/v乙醇、95％v/v乙醇、80％v/v乙醇、70％v/v乙醇、纯水中各5min。
4.抗原修复：在修复盒中加入pH＝6.0的柠檬酸钠缓冲液，微波加热至沸腾，切片置于耐高温的塑料架上，小心放入修复盒中，微波中火加热15min。加热结束后，取出修复盒，于室温下自然冷却。弃去抗原修复液，将切片用PBS冲洗3次，每次3min。
5.消除内源性过氧化物酶：将切片移入湿盒中，加入新鲜配制的3％v/v双氧水，室温孵育10分钟，PBS冲洗3次，每次3min。
6.封闭：吸水纸吸干PBS，在玻片上滴加正常山羊血清封闭液，室温封闭30min。
7.一抗孵育：吸水纸吸掉封闭液，每张玻片滴加足够量的稀释好的一抗(CXCL13，R&D systems，#Q53X90，羊多克隆抗体，稀释比例1:200(体积比))，放入湿盒，4℃孵育过夜。
8.二抗孵育：取出切片，PBS冲洗3次，每次3分钟。将切片置于湿盒，滴加二抗工作液，室温孵育1h，PBS冲洗3次，每次3min。
9.显色：于切片上滴加DAB显色液，于显微镜下不断观察显色程度，显色5-10分钟，PBS冲洗1min。
10.复染：苏木素室温复染1min。
11.分化：0.5％v/v盐酸酒精室温分化10s。
12.返蓝：1％v/v氨水室温返蓝10，PBS冲洗1min。
13.脱水、透明、封片、镜检。
免疫组化染色检测PD-L1的具体步骤如下：
1.烤片：石蜡组织切片入放入60℃烤箱中烤片1.5h。
2.脱蜡：切片在二甲苯中放置10min，更换二甲苯，再放置10min。
3.水化：切片依次放入100％v/v乙醇、100％v/v乙醇、95％v/v乙醇、80％v/v乙醇、70％v/v乙醇、纯水中各5min。
4.抗原修复：在修复盒中加入pH＝6.0的柠檬酸钠缓冲液，微波加热至沸腾，切片置于耐高温的塑料架上，小心放入修复盒中，微波中火加热15min。加热结束后，取出修复盒，于室温下自然冷却。弃去抗原修复液，将切片用PBS冲洗3次，每次3min。
5.消除内源性过氧化物酶：将切片移入湿盒中，加入新鲜配制的3％v/v双氧水，室温孵育10分钟，PBS冲洗3次，每次3min。
6.封闭：吸水纸吸干PBS，在玻片上滴加正常山羊血清封闭液，室温封闭30min。
7.一抗孵育：吸水纸吸掉封闭液，每张玻片滴加足够量的稀释好的一抗(PD-L1，克隆号E1L3N，CST，#13684，兔多克隆抗体，稀释比例1:100)，放入湿盒，4℃孵育过夜。
8.二抗孵育：取出切片，PBS冲洗3次，每次3分钟。将切片置于湿盒，滴加二抗工作液，室温孵育1h，PBS冲洗3次，每次3min。
9.显色：于切片上滴加DAB显色液，于显微镜下不断观察显色程度，显色5-10分钟，PBS冲洗1min。
10.复染：苏木素室温复染1min。
11.分化：0.5％v/v盐酸酒精室温分化10s。
12.返蓝：1％v/v氨水室温返蓝10，PBS冲洗1min。
13.脱水、透明、封片、镜检。
结果表明，在CXCL13高表达的患者中，83％为有效患者(PR+SD)，其中39％的患者对免疫治疗有部分反应(PR:Partial response)，而44％的患者维持稳定状态(SD:Stable disease)，只有17％的患者出现了疾病进展(PD:Progress disease)。而在CXCL13低表达的患者中，却有高达63％的患者出现了疾病进展(图5)。以上结果证明，CXCL13的表达水平与患者对免疫治疗的响应呈正相关，即，CXCL13表达水平越高，则免疫治疗效果越好；CXCL13表达 水平越低，则免疫治疗效果越差。而通过PD-L1的染色进行疗效预测，发现在PD-L1≥1的患者中，71.4％为有效患者，28.6％的患者出现了疾病进展。在PD-L1<1的患者中，58.3％有效患者，41.7％的患者出现了疾病进展(图3)。以上结果表明，与PD-L1相比，CXCL13的表达水平能够更准确地反映、预测患者的免疫治疗效果。
进一步利用这两个指标对患者的无复发生存期进行比较发现，PD-L1高表达患者的无复发生存虽然略好于低表达患者，但统计意义并不显著(图4)。表明PD-L1表达的强弱并不能对患者的无复发生存进行预测。而CXCL13高表达患者的无复生存则显著优于CXCL13低表达患者(图6)。表明CXCL13高表达是患者预后好的明确指标。

Claims (6)

  1. CXCL13检测剂在制备预测免疫治疗效果的试剂盒中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述CXCL13检测剂用于检测CXCL13在肿瘤特异T细胞中的表达水平。
  3. 根据权利要求2所述的用途，其特征在于，所述肿瘤特异T细胞为CD4肿瘤特异T细胞或CD8肿瘤特异T细胞。
  4. 一种用于预测免疫治疗效果的试剂盒，其包括用于检测CXCL13在肿瘤特异T细胞中的表达水平的CXCL13检测剂。
  5. 一种预测免疫治疗效果的方法，其特征在于，所述方法通过检测CXCL13在肿瘤特异T细胞中的表达水平来预测免疫治疗效果。
  6. 根据权利要求5所述的方法，所述肿瘤特异T细胞为CD4肿瘤特异T细胞或CD8肿瘤特异T细胞。
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