Research Progress on Effects of Gut Microbiome on Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer
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摘要:
随着免疫治疗领域的快速发展，越来越多的免疫检查点抑制剂被应用于临床。免疫治疗为结直肠癌晚期转移患者提供了一种新的治疗选择。研究证实，错配修复缺陷/高度微卫星不稳定（dMMR/MSI-H）状态的晚期转移性结直肠癌患者对免疫治疗更敏感，有较为客观及持续的临床反应。在肿瘤免疫治疗的应答中，肠道菌群被证实有一定的调节作用，部分细菌可通过免疫系统或机体代谢功能来影响免疫检查点抑制剂的疗效。随着研究的进展，肠道菌群不仅有望成为结直肠癌免疫治疗的疗效预测性生物标志物，也可能成为影响结直肠癌免疫治疗结果的关键调控因素，在今后的临床治疗中，为更多的晚期结直肠癌患者使用免疫检查点抑制剂获益带来可能性。
Abstract:With the rapid development of immunotherapy, an increasing number of immune checkpoint inhibitors have been used in clinical settings. Immunotherapy provides a new treatment option for patients with advanced colorectal cancer metastasis. Studies have confirmed that patients with metastatic colorectal cancer with dMMR/MSI-H status are more sensitive to immunotherapy and have a more objective and sustained clinical response than their counterparts. Gut microbiome has been proved to play a certain regulatory role in tumor immunotherapy response, and some bacteria can affect the efficacy of immune checkpoint inhibitors through the immune system or metabolic function of the body. With the progress of the study, the gut microbiome is expected to become not only the predictive biomarkers of curative effect of colorectal cancer immunotherapy, but it can also be a key regulatory factor influencing the results of colorectal cancer immunotherapy. For future clinical treatment, the use of immune checkpoint inhibitors may benefit patients with advanced colorectal cancer.
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Key words:
- Colorectal cancer /
- Immune checkpoint inhibitors /
- Gut microbiome /
- Curative effect
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0 引言
在过去20年里, 局部肿瘤的冻融治疗已经有了长足的发展, 主要集中在肝癌[1]、转移性癌[2]、肾癌[3]、前列腺癌[4]等实体瘤治疗中。同时, 越来越多的报道表明, 冻融治疗可以破坏肿瘤, 增强或诱导细胞免疫或抗肿瘤免疫应答[5-7]。此外, 肿瘤细胞的破坏和溶解可能成为炎性反应的重要介质[8]。
库普弗细胞(Kupffer cells, KCs)是数量最大的免疫细胞, 占肝脏巨噬细胞的80%~90%, 也是单核吞噬细胞系统的重要组成部分, 在肝脏巨噬细胞的发生发展中起着重要的作用[9]。KCs的激活与多种细胞因子的分泌密切相关, 这些细胞因子参与免疫和促炎或抗炎反应[10]。KCs自身还具有分泌炎性因子的功能, 参与肝脏中各种重要的生理和病理过程, 如炎性反应、脂质代谢、移植免疫等[11]。
因此, 有必要研究冻融后KCs分泌功能的特征, 帮助我们治疗肝癌, 促进患者的早期康复, 为肝癌冻融治疗能提高自身免疫功能的学说提供理论依据。为此, 本研究通过体外细胞实验, 从兔肝中提取KCs并进行了体外培养, 应用NF-κB抑制剂吡咯烷二硫代氨基甲酸酯(PDTC)阻断NF-κB信号通路后, 观察KCs的分泌功能变化, 探索冻融治疗引起KCs功能变化的机制。
1 材料与方法
1.1 材料
NF-κB抑制剂PDTC购自美国BioVision公司; 胎牛血清购自杭州四季青生物工程材料有限公司; 低糖DMEM完全培养基购自美国ATCC公司; 0.4%锥虫蓝溶液购自美国Sigma公司; GAPDH购自英国Abcam公司; 蛋白Marker(10~170 kDa)购自立陶宛Fermentas公司; 0.45 μm PVDF膜购自美国Millipore公司; SDS-PAGE凝胶制备试剂盒、蛋白抽提试剂盒、BCA蛋白浓度测定试剂盒、ECL化学发光试剂盒、PMSF(100 mmol/L)、磷酸化蛋白酶抑制剂、5×蛋白上样缓冲液、10×丽春红染液和抗体洗脱液均购自武汉拓捷生物公司; Tris和甘氨酸购自国药集团化学试剂有限公司(上海); 动物麻醉剂(速眠新Ⅱ)购自中国动物保健品有限公司(北京), 其他试剂由中国人民解放军中部战区总医院医学实验科提供。
1.2 方法
1.2.1 KCs细胞悬液的制备
经肌肉注射速眠新Ⅱ(0.2 ml/kg)麻醉后, 对其进行消毒、开腹、门静脉暴露和固定插管并打开胸腔。根据Zeng等[12]制备KCs细胞悬液的方法, 对下腔静脉结扎后, 快速切割、断裂部分肝脏, 用PBS冲洗两次。取肝悬液离心, 取上清液。充分悬浮后, 将上述肝细胞悬液移入含30%和60%细胞分离液的离心管中, 以800 g(20℃)缓升缓降离心20 min, 离心后可见乳白色细胞层。收集细胞层, 继续培养。
1.2.2 构建低温和冻融坏死的肿瘤细胞攻击KCs的细胞模型
模拟冻融治疗时体内KCs受到的主要攻击因素是低温和冻融坏死物质, 构建体外细胞模型。将浓度为1×106/ml的KCs悬浮液用5 ml一次性塑料吸管分为不同的培养瓶, 每瓶加入5 ml。实验分为8组, 每组9瓶:(1)对照组:KCs正常培养37℃; (2)0℃组:模拟冻融治疗时冰球边缘温度, 将培养瓶置于0℃环境中20 min, 取出放回37℃孵化器。5 min后, 将培养瓶置于0℃环境中20 min, 再放入37℃培养箱中, 培养6 h后, 进行实验; (3)5℃低温组和10℃低温组:模拟冻融治疗时冰球边缘距离0.5 cm和2 cm的温度。实验方法与0℃组相同, 但放置培养瓶的温度环境不同。5℃组在5℃环境中放置2次20 min, 10℃组在10℃环境中放置2次20 min; (4)冻融坏死物质组:冻融治疗后第3天将治疗中心肿瘤组织(人肝癌HepG2细胞购于中国科学院上海科学院资源中心, 于中国人民解放军中部战区总医院医学实验科内进行传代培养)制成1%细胞悬液, 在KCs培养瓶中加入2 ml, 其余培养条件与对照组相同; (5)联合刺激组:按不同温度(0℃、5℃、10℃)放置的KCs培养瓶分为3组。各组再加入冻融肿瘤坏死细胞悬液, 其浓度与冻融坏死物质组相同, 实验方法分为0℃、5℃和10℃组。
1.2.3 干预措施
以上8组各设1个平行组。将PDTC加入培养基中, NF-κB抑制剂最终浓度为100 μmol/L。
1.2.4 KCs分泌功能的检测
参考文献中的方法[13], 采用ELISA法检测KCs上清液中肿瘤坏死因子-α(TNF-α)、白细胞介素-1(IL-1β)和干扰素-γ(INF-γ)的浓度。各组采用ELISA法检测细胞培养液中的IFN-γ、IL-1β、TNF-α的浓度。
1.2.5 NF-κB蛋白测定
各组培养6 h后, 用Western blot法检测各组NF-κB蛋白的表达, 用定量软件处理系统分析靶带的吸光度值。Western blot检测方法如文献所述[14]。用鼠抗NF-κB抗体(sc-109, Santa Cruz生物技术, 美国圣克鲁斯州)进行印迹检测, 计算靶带的吸光度值。
1.3 统计学方法
采用SPSS19.0统计学软件进行统计学分析。计数资料以均数±标准差(
2 结果
2.1 KCs分泌功能测试
(1) 无抑制剂组与对照组比较:低温组(0℃、5℃、10℃)和10℃冻融坏死物质组培养1 h时KCs细胞分泌炎性因子水平差异无统计学意义(P>0.05), 冻融坏死物质组与联合刺激组比较KCs细胞分泌炎性因子水平差异有统计学意义(P < 0.05), 10℃冻融坏死物质组与对照组比较KCs细胞分泌炎性因子水平差异有统计学意义(P < 0.05)。各组培养1 h, 与对照组比较(P < 0.01), 差异有统计学意义。(2)无抑制剂组KCs细胞分泌炎性因子水平与培养时间的相关性:随着培养时间的延长(1、2、3 h), 炎性因子的分泌水平显著升高, 差异有统计学意义(χ2=10.750, P=0.005)。(3)抑制剂组与对照组比较:各组KCs细胞分泌炎性因子水平比较(P>0.05), 差异无统计学意义; 组内KCs细胞分泌炎性因子水平比较, 差异无统计学意义(χ2=2.25, P=0.325)。(4)有抑制剂组和无抑制剂组KCs细胞分泌炎性因子水平比较, 两组在相同条件下(对照组除外)均有统计学意义(P < 0.01)。
KCs分泌功能结果显示, 用低温或冻融坏死物或联合刺激KCs后培养1 h, 炎性因子的分泌增加(P < 0.01), 低温和冻融坏死产物组的联合刺激具有叠加作用。此外, 随着培养时间的延长(1、3、6 h), 炎性因子的分泌水平显著升高(χ2=10.750, P=0.005), 有级联放大的趋势。在PDTC存在下, 8组间炎性因子的分泌水平差异无统计学意义(P=0.325)。延迟培养时间, 各组KCs细胞分泌炎性因子水平无变化, 见表 1~2。
表 1 无抑制剂组的KCs分泌功能测试结果Table 1 Test results of secretion function of Kupffer cells (KCs) without inhibitor
表 2 有抑制剂组的KCs分泌功能测试结果Table 2 Test results of secretion function of KCs with inhibitor
2.2 NF-κB蛋白表达
低温刺激对NF-κB蛋白的表达无显著影响, 而对照组与低温组之间比较差异无统计学意义(P>0.05)。联合刺激组和冻融坏死物质组NF-κB蛋白表达明显上调(P < 0.05), 差异有统计学意义。而抑制剂组NF-κB蛋白的表达无明显变化, 其线型几乎呈直线状, 见图 1~3。
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图 3 NF-κB蛋白的表达Figure 3 Expression of NF-κB protein1: Control group; 2: 0℃; 3: 5℃; 4: 10℃; 5: Frozen necrosis; 6: 0℃+Frozen necrosis; 7: 5℃+Frozen necrosis; 8: 10℃+Frozen necrosis3 讨论
KCs凭其吞噬和分泌功能, 参与了肝脏多种重要的生理和病理过程, 如清除坏死细胞和组织碎片, 诱导炎性反应、参与脂质代谢、移植免疫等[15-17]。KCs功能受内毒素、脂多糖、坏死组织或细胞、应激等多种因素的影响[10]。活化的KCs能产生多种细胞因子, 包括TNF-α、IL-1β和INF-γ等, 对靶细胞产生杀伤作用, 从而发挥其生物学作用[18]。冻融治疗主要利用温度急剧变化, 破坏肿瘤细胞, 同时对治疗区周围组织产生低温刺激, 诱发机体应激反应。而应激和坏死肿瘤细胞释放的如水解蛋白酶等细胞有害物均可引起KCs的变化[19]。
KCs受到低温或冻融坏死物质刺激后, 可促进炎性因子的分泌, 如TNF-α、IL-1β和INF-γ, 这些炎性因子可诱导炎性细胞聚集、介导炎性反应和清除坏死细胞或组织碎片[20], 这一反应过程可能是冻融治疗后残存肿瘤的一个杀伤机制。此外, 本研究还发现, 在培养瓶中加入NF-κB抑制剂后, 低温组、冻融坏死物质组和联合刺激组的炎性细胞因子水平均无变化, 说明用NF-κB抑制剂可以抑制炎性因子的分泌过程。同时, 还发现TNF-α、IL-1β和INF-γ的浓度与KCs上清液中NF-κB蛋白表达呈正相关, 所以冻融治疗后KCs的分泌功能可能通过NF-κB信号通路调控。
NF-κB是一个转录因子家族, 调控大量参与细胞存活、炎性反应和免疫反应等重要生理过程的基因。最近有研究表明, NF-κB的组成型表达与多种类型的癌症有关[21]。NF-κB信号通路也是炎性反应相关的癌症发生的重要因素[22]。本研究通过对NF-κB信号通路相关蛋白的检测, 探讨了KCs诱导炎性反应的机制。NF-κB是细胞内重要的核转录因子, 是细胞免疫和炎性反应的重要组成部分[23], 它参与多种基因的表达和调控[24]。关于KCs活化的信号转导途径, 认为NF-κB是调节KCs活化的关键因素[25], NF-κB在某些细胞信息转录调控中起着关键作用[26], 它是细胞活化的标志, 也是激活炎性反应的重要因素[27]。有研究证实, NF-κB信号通路是肿瘤治疗的潜在靶点[28]。如果这一信号通路在冻融治疗引起的免疫功能变化中发挥类似作用, 将有助于探讨冻融治疗后免疫功能变化的机制。其最直接的判断方法即阻断NF-κB信号通路。吡咯烷二硫代氨基甲酸酯在NF-κB活化通道的不同水平发挥抑制NF-κB蛋白表达的作用, 从而阻断NF-κB信号通路, 阻断是否成功可以通过检测NF-κB信号通路中的通路终末蛋白NF-κB蛋白的表达情况判断。
在KCs培养瓶中加入冻融坏死物质, 其中含有细胞毒素等刺激信号, 这些信号可与KCs膜表面受体结合, 如与清道夫受体(scavenger receptor, SR)结合, 被吞噬到KCs内; 再经过多级级联反应, 使NF-κB的抑制蛋白(IKB)的上游激酶IKB激酶(IKB kinse, IKK)磷酸化而激活, IKK使IKB降解。P50有核定位信号, 当失去了IKB的束缚后, P50会携载RelA(P65)向核内迁移, P65与细胞核内基因启动子或增强子区域上的顺势反应元件结合, 从而调控靶基因的转录, 诱导NF-κB mRNA的产生, 最后转录、产生和释放各种细胞因子(如TNF-α、IL-1β等)[29]。本研究检测结果提示加入冻融坏死物质后, NF-κB蛋白表达上调, 炎性因子分泌增加, 说明NF-κB信号通路的存在; 而加入PDTC后, PDTC作为一种抗氧化剂, 可以在NF-κB活化通道的不同水平发挥抑制NF-κB蛋白表达的作用, 如阻止上游IKK磷酸化, 从而阻止NF-κB信号通路, 抑制NF-κB蛋白表达, 导致炎性因子分泌减少。反向证明冻融治疗后KCs的变化可能通过NF-κB信号通路发挥作用。
综上所述, 冻融治疗可以改变KCs周围的微环境, 刺激KCs分泌细胞因子的功能, 从而诱导炎性反应, 清除肿瘤细胞。另外还证实KCs分泌功能变化可能是通过NF-κB信号通路转导的。
Competing interests: The authors declare that they have no competing interests.作者贡献：王艺洁：构思、撰写论文，文献检索张港玮：文献检索、整理徐超：审核、校对论文姚庆华：审核论文 -
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1. 胡馨予，董睿陶，李志平，杜琳，刘艳. 大波斯菊苷抗肝癌活性及作用机制. 肿瘤防治研究. 2021(03): 248-254 . 
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