Change in follicular helper T cells in the peripheral blood and spleen of rats after Echinococcus multilocularis infection

Yaogang ZHANG; Jianhua LI; Jing HOU; Li SUN; Meiyuan TIAN; Yuan JIANG; Dengliang HUANG; Tao ZHANG; Yanyan MA; Haining FAN

doi:10.3969/j.issn.1001-5256.2021.07.035

Volume 37 Issue 7

Jul. 2021

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Article Navigation > Journal of Clinical Hepatology > 2021 > 37(7): 1657-1661

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Change in follicular helper T cells in the peripheral blood and spleen of rats after Echinococcus multilocularis infection

DOI: 10.3969/j.issn.1001-5256.2021.07.035

Yaogang ZHANG^{1, 2},
Jianhua LI¹,
Jing HOU¹,
Li SUN¹,
Meiyuan TIAN¹,
Yuan JIANG¹,
Dengliang HUANG¹,
Tao ZHANG^{1, 3},
Yanyan MA^{1, 2
,
,},
Haining FAN^{1, 2
,
,}

1.
Central Laboratory of Qinghai University Affiliated Hospital, Xining 810000, China
2.
Qinghai Province Key Laboratory of Hydatid Disease Research, Xining 810000, China
3.
School of Clinical Medicine, Qinghai University, Xining 810000, China

Research funding:

Qinghai University Affiliated Hospital for Young and Middle-aged Project (ASRF-2018-YB-01);

Qinghai Provincial Department of Science and Technology Major Science and Technology Project (2016-SF-A5);

National Natural Science Foundation of China (81960129)

Received Date: 2020-12-10
Accepted Date: 2021-01-12
Published Date: 2021-07-20

Abstract

Abstract

Objective To investigate the level of follicular helper T (Tfh) cells in the peripheral blood and spleen of the host after Echinococcus multilocularis infection and its association with the progression of echinococcosis. Methods A total of 20 Sprague-Dawley rats were randomly divided into normal control group and model group, with 10 rats in each group. The rats in the model group were inoculated with about 2000 protoscoleces in the right liver under direct-view laparotomy, and those in the control group were not given any treatment. The rats were anesthetized and sacrificed after 3 months to collect peripheral blood and spleen cells, and with CD4⁺CXCR5⁺PD1⁺ as the marker of Tfh cells, flow cytometry was used to measure the level of Tfh cells in peripheral blood and spleen. The t-test was used for comparison of Tfh cells between the two groups. Results After 3 months of Echinococcus multilocularis infection, marked lesions were observed in the liver, and HE staining showed the presence of protoscoleces in the lesions. The proportion of CD4⁺CXCR5⁺PD1⁺Tfh cells in CD4⁺ cells in peripheral blood was 25.63%±3.47% in the model group and 11.12%±2.94% in the normal control group (t=10.230, P < 0.001), a nd the model group had a significantly lower proportion of CD4⁺CXCR5⁺PD1⁺Tfh cells in all cells than the normal control group (0.08%±0.02% vs 0.18%±0.05%, t=5.520, P < 0.001). For the model group, the proportion of CD4⁺CXCR5⁺PD1⁺Tfh cells in all cells in the spleen decreased to 3.00%±0.42%, which was significantly lower than the proportion of 5.30%±1.40% in the normal control group (t=4.769, P < 0.001). Conclusion Tfh cells in peripheral blood are closely associated with the progression of echinococcosis and are expected to become an indicator of Echinococcus multilocularis infection.
- Echinococcosis, Hepatic,
- T-Lymphocytes,
- Rats, Sprague-Dawley

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原发性肝癌作为临床最为常见的恶性肿瘤之一，具有较高的发病率和死亡率，是最为常见的癌症相关性死亡原因之一^[1-2]。由于原发性肝癌发病隐匿，患者缺乏早期典型的临床症状，大部分患者在临床确诊时已经处于疾病的中晚期阶段，能够进行根治性手术切除的患者比例甚至不足20%。经肝动脉化疗栓塞术(transcatheter arterial chemoembolization, TACE)是中晚期原发性肝癌患者治疗的主要手段，可有效改善患者临床预后^[3-5]。然而，当前仍缺乏评价中晚期肝癌TACE术后预后的有效方式。研究^[6-7]显示，表皮生长因子受体(epidermal growth factor receptor, EGFR)信号通路是原发性肝癌发生发展的关键。KRAS基因属于Ras原癌基因家族中的一员，不仅是抗EGFR靶向治疗选择的重要依据，同时也可能成为患者预后的预测因子。本研究探讨KRAS基因状态对TACE治疗中晚期肝癌患者预后的预测价值。

1. 资料与方法

1.1 研究对象

选择2017年4月—2020年5月在海南省第三人民医院接受TACE治疗的中晚期肝癌患者为研究对象。纳入标准：(1)患者均经穿刺活检，临床病理诊断为原发性肝癌患者；(2)心、肺、肾等机体主要器官功能无明显障碍患者；(3)巴塞罗那肝癌临床分期(BCLC)B期或C期患者；(4)肝功能Child-Pugh分级为A级或B级患者；(5)无法接受外科手术治疗切除患者；(6)卡氏(KPS)评分＞60分；(7)术前未接受其他治疗。排除标准：(1)合并严重凝血功能障碍患者；(2)大量腹水或顽固性腹水患者；(3)有TACE治疗禁忌证患者；(4)合并远处转移患者。

1.2 TACE治疗方法

使用Seldinger法穿刺患者股动脉，插管直至肝总动脉进行造影，以明确肿瘤大小、数目、位置。以微导管超选择插管至支配肝癌病灶的主要供血动脉内，将化疗药物(氟尿嘧啶750 mg/m²，奥沙利铂60 mg/m²)稀释液缓慢注入，然后使用15~25 mL 40%碘化油栓塞肿瘤末梢血管。若有必要可使用明胶海绵颗粒，以尽可能完全阻断患者肿瘤血供。根据患者肿瘤大小、数量以及患者肝功能具体情况确定碘化油及栓塞剂的使用剂量。此外，根据患者情况决定TACE治疗次数，本研究患者治疗2~3次。

1.3 KRAS基因检测

TACE手术前，在超声引导下对肝癌组织进行穿刺取材，取5 g左右肿瘤组织，按照QIAamp DNAFFPF Kit试剂盒(Qiagen公司)步骤提取肿瘤组织DNA，使用紫外分光光度计检测提取DNA浓度，然后调节浓度至100 μg/mL，-20 ℃保存待测。扩增KRAS基因12/13号密码子特需特异性引物，根据文献^[8]报道，引物序列，正义：5′-CTGTATCAAAGAATGGTCCTGCAC-3′，反义：5′-CTGTATCAAAGAATGGTCCTGCAC-3′。引物及Premix PCR试剂盒购于宝生物工程(大连)有限公司，PCR反应体系50 μL。PCR反应条件：94 ℃ 5 min，94 ℃ 30 s、60 ℃ 30 s、70 ℃ 40 s，共完成30个循环，使用1.5%琼脂糖凝胶电泳分析PCR产物，选取PCR阳性凝胶条带作为目的片段，使用QIAquick PCR Purification Kit(Qiagen公司)对PCR产物回收，然后送至上海基因技术有限公司进行测序分析。

1.4 随访

所有患者在接受TACE术后，每月复查肝功能、AFP、肝脏增强CT或MRI，以评估患者肿瘤控制情况以及术后复发情况，记录患者无进展生存期(PFS)以及总体生存期(OS)。PFS指的是从患者TACE术后到观察到疾病进展或发生死亡(由于任何原因)之间的时间；OS指的是从患者TACE术后到患者死亡(由于任何原因)之间的时间。

1.5 统计学方法

采用统计学软件SPSS 25.0处理数据。计量资料以x±s表示，两组间比较采用t检验，计数资料两组间比较采用χ²检验，生存分析绘制Kaplan-Meier生存曲线，生存曲线比较采用Log-rank检验，对可能影响患者预后的各因素进行Cox回归分析。P＜0.05为差异具有统计学意义。

2. 结果

2.1 KRAS基因突变检测结果

97例患者中男61例、女36例，年龄30~78岁，平均(56.48±12.31)岁。肿瘤最大径2.89~9.74 cm，平均(7.19±2.08)cm；肿瘤单个89例、≥2个18例。在本组97例晚期肝癌患者中，共检出KRAS基因突变患者34例(35.05%)，其中检出12号密码子突变患者21例(61.76%)，13号密码子突变患者13例(38.24%)。在检出KRAS基因突变患者中，均为单个碱基的点突变，而并未检出两个或两个以上碱基突变或其他形式的突变(图 1)。

图 1 KRAS基因12、13密码子序列突变图谱

注：a, KRAS基因12、13密码子野生型基因序列；b, KRAS基因12密码子GGT→GAT突变；c, KRAS基因12密码子GGT→GTT突变；d, KRAS基因13密码子GGC→GAC突变。

Figure 1. Mutation map of KRAS gene codons 12 and 13

下载: 全尺寸图片幻灯片

2.2 KRAS基因突变状态与患者临床病理特征的关系

KRAS基因突变型与野生型比较，肝内转移、肿瘤数目的差异均有统计学意义(χ²值分别为3.965、6.593，P值均＜0.05)(表 1)。

表 1 KRAS基因突变状态与患者临床特征的关系

Table 1. The relationship between KRAS gene mutation status and clinical characteristics of patients

临床资料	KRAS突变型 (n=34)	KRAS野生型 (n=63)	统计值	P值
性别(例)			χ²=0.370	0.543
男	20	41
女	14	22
年龄(岁)	55.12±14.21	56.93±10.04	t=0.730	0.468
乙型肝炎病史(例)			χ²=0.057	0.811
阴性	30	56
阳性	4	7
ALT(U/L)	49.85±14.20	51.24±15.22	t=0.439	0.662
凝血酶原时间(s)	12.83±1.84	13.02±2.10	t=0.443	0.659
总胆红素(mmol/L)	17.94±3.73	18.05±3.16	t=0.153	0.878
白蛋白(g/L)	40.27±6.49	40.53±5.98	t=0.198	0.843
AFP(ng/L)	438.95±109.32	409.64±97.58	t=1.353	0.179
肿瘤大小(cm)	7.39±2.30	7.02±2.15	t=0.789	0.432
肝硬化(例)			χ²=0.035	0.852
有	27	49
无	7	14
肝内转移(例)			χ²=3.965	0.047
有	16	17
无	18	46
肿瘤数目(例)			χ²=6.593	0.010
单个	23	56
多个	11	7
腹水(例)			χ²=0.057	0.811
无	31	55
有	3	8
Child-Pugh分级(例)			χ²=0.056	0.812
A	24	43
B	10	20
BCLC分期(例)			χ²=0.074	0.785
B	22	39
C	12	24

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2.3 KRAS基因突变状态与患者生存分析

对本组97例患者进行追踪随访显示，KRAS基因野生型患者平均PFS为11.35个月，突变型患者平均PFS为19.65个月；KRAS基因野生型患者平均OS为19.18个月，突变型患者平均OS为26.54个月。Kaplan-Meier生存分析结果显示，KRAS基因野生型患者PFS及OS均显著优于KRAS突变型(P值均＜0.05)(图 2、3)。

图 2 KRAS基因状态与患者PFS的关系

Figure 2. Relationship between KRAS gene status and progression-free survival analysis of patients

下载: 全尺寸图片幻灯片

图 3 KRAS基因状态与患者OS的关系

Figure 3. Relationship between KRAS gene status and overall survival analysis of patients

下载: 全尺寸图片幻灯片

2.4 影响患者预后的Cox分析

对可能影响患者总体生存预后的各因素进行Cox分析，结果显示，KRAS基因状态(RR=18.273, 95%CI：5.584~98.305)、肝内转移(RR=11.475, 95%CI：3.029~56.490)、肿瘤数目(RR= 10.038, 95%CI：2.973~19.328)、BCLC分期(RR=12.384, 95%CI：2.385~29.305)与患者预后密切相关，为影响患者总体生存预后的重要因素(P值均＜0.05)(表 2)。

表 2 影响患者预后的Cox分析

Table 2. Cox analysis affecting patient outcomes

自变量	RR	95%CI	P值
性别(男性=0，女性=1)	2.734	0.983~7.935	0.283
年龄(≥60岁=0，＜60岁=1)	3.038	0.627~10.293	0.276
KRAS基因状态(突变型=0，野生型=1)	18.273	5.584~98.305	0.001
乙型肝炎病史(有=0，无=1)	5.484	0.719~9.380	0.193
ALT(≥40 U/L=0，＜40 U/L=1)	2.079	0.417~12.953	0.389
凝血酶原时间(≥12 s=0，＜12 s=1)	1.092	0.271~9.182	0.849
总胆红素(≥18 nmol/L=0，＜18 nmol/L=1)	1.684	0.495~7.293	0.711
白蛋白(≥40 g/L=0，＜40 g/L=1)	2.087	0.408~11.235	0.419
AFP(≥400 ng/L=0，＜400 ng/L=1)	2.193	0.602~11.293	0.619
肿瘤大小(≥7 cm=0，＜7 cm=1)	2.183	0.485~7.304	0.280
肝硬化(有=0，无=1)	1.804	0.198~10.237	0.695
肝内转移(有=0，无=1)	11.475	3.029~56.490	0.018
肿瘤数目(单发=0，多发=1)	10.038	2.973~19.328	0.021
腹水(有=0，无=1)	2.013	0.421~8.106	0.174
Child-Pugh分级(A=0，B=1)	2.189	0.569~7.491	0.209
BCLC分期(B=0，C=1)	12.384	2.385~29.305	0.011

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3. 讨论

目前，TACE已经成为无法外科切除中晚期肝癌患者的首选治疗方式。肝癌的主要供血为肝动脉供血。经肝动脉碘油注射后，碘油可在肝癌的组织间隙、肝窦以及细小血管内选择性停滞，从而导致癌细胞失去血液供应而导致肿瘤组织缺血坏死^[9-10]；在碘油中混合化疗药物，从而使化疗药物在肿瘤组织中缓慢释放，延长了化疗药物与肿瘤细胞之间的接触时间，进而显著提高化疗药物治疗效果，同时可显著减小化疗药物对患者全身的不良影响，并阻断肿瘤血供，引起肿瘤组织发生缺血性坏死，进一步增加抗肿瘤疗效^[11-12]。研究提出^[13-14]，采取非手术多模式治疗，尤其对于原发性肝癌患者采取TACE治疗，可有效延长患者生存期，在中晚期肝癌的治疗中具有重要作用。

原发性肝癌是多基因、多分子、多通路间相互作用的结果，因此检测原发性肝癌患者基因突变状况，对于患者治疗反应以及生存预后具有预测价值，从而有助于实现精准化治疗的目的^[15-16]。KARS基因突变在原发性肝癌患者中具有着较高的发生率。研究^[17-18]显示，原发性肝癌的发生是一种多步骤过程，而在肿瘤恶性发生的整个过程中，均与KRAS基因突变有关。有研究^[19-20]认为，KRAS基因突变被认为是原发性肝癌发生的启动性因子，尤其G-A碱基突变，可能在多种恶性肿瘤发生中具有重要作用。

本研究结果显示，在本组97例中晚期肝癌患者中，共检出KRAS基因突变患者34例(35.05%)，其中检出12号密码子突变患者21例(61.76%)，13号密码子突变患者13例(38.24%)，且检出的患者均为单个碱基突变。本组结果与相关研究报道结果基本一致^[21]。KRAS基因突变率接近35%，是一种较为常见的基因突变形式。此外，KRAS基因突变与患者肝硬化、肝内转移、肿瘤数目有关。提示KRAS基因突变的存在可能与肝癌疾病的发生发展具有一定的内在联系，从而为KRAS突变可能成为预测患者治疗预后的因素提供一定的基础。

Kaplan-Meier生存分析结果显示，KRAS基因野生型患者PFS及OS均显著优于KRAS突变型。表明了KRAS基因状态与患者TACE术后生存状况密切相关。KRAS基因野生型患者可受上游EGFR信号通路的调控，而当KRAS基因发生点突变时，导致该基因编码P21蛋白的空间结构发生了相应的变化，不再受上游EGFR信号的调控。KRAS基因突变亚型不同，可能也会导致该基因的空间构象发生变化，引起相应的调节细胞内信号通路不同，从而影响化疗药物的结合位点，也可能导致患者对化疗药物的敏感性有所差别，进而影响患者预后。

同时，本研究进一步对可能影响患者术后预后的各因素进行Cox回归分析，结果显示，KRAS基因状态、肝内转移、肿瘤数目、BCLC分期进入回归模型，为影响患者总体生存预后的重要因素。肿瘤数目、肝内转移以及BCLC分期均可有效提示原发性肝癌患者自身状态及肿瘤的进展情况，故而可影响患者预后，而KRAS基因状态同样进入了Cox回归模型，提示KRAS基因状态也对患者临床预后有着重要的影响。此外，通过Kaplan-Meier生存分析以及Cox多因素分析，进一步确定了KRAS基因状态与患者TACE术后预后具有密切关系，可能成为预测患者术后预后的重要因素之一。KRAS基因突变，可能是导致患者术后预后较差的因素，因此关注肝癌TACE患者KRAS基因状态，对于提前制订相关治疗计划具有重要价值。

但是由于本研究纳入样本量相对较小，研究结果可能存在一定的偏差，后期研究将进一步扩大研究样本量，以获得更为可靠的临床研究数据。

综上所述，KRAS基因突变在原发性肝癌中较为常见，与患者TACE术后不良预后密切相关，可成为患者临床预后监测的潜在指标。

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Change in follicular helper T cells in the peripheral blood and spleen of rats after Echinococcus multilocularis infection

DOI: 10.3969/j.issn.1001-5256.2021.07.035