高级搜索

免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展

王艺洁, 张港玮, 徐超, 姚庆华

王艺洁, 张港玮, 徐超, 姚庆华. 免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展[J]. 肿瘤防治研究, 2022, 49(11): 1184-1189. DOI: 10.3971/j.issn.1000-8578.2022.22.0429
引用本文: 王艺洁, 张港玮, 徐超, 姚庆华. 免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展[J]. 肿瘤防治研究, 2022, 49(11): 1184-1189. DOI: 10.3971/j.issn.1000-8578.2022.22.0429
WANG Yijie, ZHANG Gangwei, XU Chao, YAO Qinghua. Research Progress on Effects of Gut Microbiome on Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(11): 1184-1189. DOI: 10.3971/j.issn.1000-8578.2022.22.0429
Citation: WANG Yijie, ZHANG Gangwei, XU Chao, YAO Qinghua. Research Progress on Effects of Gut Microbiome on Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(11): 1184-1189. DOI: 10.3971/j.issn.1000-8578.2022.22.0429

免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展

基金项目: 

国家自然科学基金青年基金 82104564

详细信息
    作者简介:

    王艺洁(1997-),女,硕士在读,医师,主要从事中西医结合治疗肿瘤的研究

    通讯作者:

    姚庆华(1974-),女,博士,主任医师,主要从事中西医结合治疗肿瘤的研究,E-mail: yaoqh@zjcc.org.cn

  • 中图分类号: R735.3+5;R735.3+7

Research Progress on Effects of Gut Microbiome on Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer

Funding: 

National Natural Science Foundation of China 82104564

More Information
  • 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.

     

  • 胶质瘤是中枢神经系统最常见的颅内原发恶性肿瘤,在所有颅内原发性肿瘤中占70%左右,其中成年人中最常见、恶性程度最高、预后最差的肿瘤是胶质母细胞瘤(glioblastoma, GBM, WHO Ⅳ)[1]。该肿瘤具有恶性增殖和高侵袭性的特点,手术及放化疗后肿瘤复发率高。

    JNK/c-Jun信号通路在调控细胞增殖、分化、凋亡和存活等基本生物学效应中扮演重要角色。JNK磷酸化下游底物c-Jun并使其激活后,可增强肿瘤细胞的增殖、侵袭和迁移能力[2-4]。MKK4和MKK7作为丝裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase, MAPKK)家族的两个成员,均可以磷酸化并激活JNK[5-7]。有报道称MKK7通过调控JNK活性调控细胞凋亡[8-10]。本课题组前期研究也发现在神经胶质瘤细胞株U251中,小分子干扰沉默MKK7表达后,可以抑制JNK/c-Jun激活[11]。为进一步了解JNK信号通路的调控机制,本研究通过采用免疫组织化学法、小分子干扰、转染及Western blot等技术检测不同组织学类型胶质瘤样本及U87细胞株中MKK7、c-Jun及其磷酸化的表达情况,分析并验证MKK7是否为直接调控JNK/c-Jun活性的关键分子。

    收集2015年11月—2017年11月广州医科大学附属第二医院病理科存档的胶质瘤石蜡包埋标本117例,其中92例胶质瘤和25例胶质母细胞瘤瘤旁正常脑组织。按2016年版“WHO中枢神经系统肿瘤的病理分类”,92例胶质瘤中:WHOⅡ:弥漫型星形细胞瘤15例,少突胶质细胞瘤5例;WHOⅢ:间变性星形细胞瘤11例,间变性少突胶质细胞瘤8例;WHOⅣ:胶质母细胞瘤53例(仅25例有相应的正常对照),患者临床病理特征见表 1。所有患者术前均未行放化疗,均知情同意。本研究得到医院医学伦理会审核批准。

    表  1  92例胶质瘤患者临床病理特征
    Table  1  Clinicopathological features of 92 gliomas patients
    下载: 导出CSV 
    | 显示表格

    人脑胶质瘤U87细胞株购自上海细胞生物学研究所中国科学院细胞库。胎牛血清、0.25%胰酶购于美国Gibco公司。培养基高糖DMEM、转染试剂RNAi MAX、opti-MEM reduced serum medium均购于美国Invitrogen公司。MKK7-1 siRNA、MKK7-2 siRNA、MKK4 siRNA、空白对照siRNA购自上海Gene Pharma公司。anti-MKK7(#4172)、anti-MKK4(#9152)、anti-p-c-Jun(#3270)、anti-GAPDH(#2118s)均购于美国Cell Signaling Technology公司。anti-c-Jun(sc-74543)购美国Santa Cruz Biotechnology公司。

    MKK4-siRNA小分子片段序列正义链:5’-GCCUUACGAAGGAUGAAUCCATT-3’,反义链:5' -UGGAUUCAUCCUUCGUAAGGCTT-3’;MKK7-siRNA1小分子片段序列正义链:5’-CCAACACGGACGUCUUCAU-3’,反义链:5’-AUGAAGACGUCCGUGUUGG-3’;MKK7-siRNA2小分子片段序列正义链:5’-GCUGGCAACAGGACAGUUU-3’,反义链:5’-AAACUGUCCUGUUGCCAGG-3’。

    所有石蜡包埋病理标本均经10%中性福尔马林固定,常规HE染色组织学观察。采用Envision二步法进行免疫组织化学染色。检测标志物:MKK7、c-Jun和p-c-Jun。4 μm厚度切片经脱蜡水化和抗原修复后,滴加一抗,放入37℃水浴箱孵育60 min,PBS冲洗后按照采用Envision检测试剂盒(DAKO公司)说明书进行,室温孵育30 min,再次PBS冲洗,DAB显色,苏木精对比染色,然后脱水、透明、封片,每例均设阳性和阴性对照。按照抗体说明书分别用膀胱组织及肺癌组织作为阳性对照,另外用PBS代替一抗作为阴性对照。

    免疫组织化学结果半定量判定:染色程度:基本不着色为0分;着色呈淡黄色为1分;着色呈黄色为2分;着色呈棕褐色为3分。染色阳性细胞百分比计数,计算阳性肿瘤细胞占总肿瘤细胞的比例,将其分为5个等级:着色阳性细胞占计数细胞≤5%为0分(-),5%~25%为1分(+), > 25%~50%为2分(++), > 50%~75%为3分(+++), > 75%为4分(++++)。将染色程度分级与染色细胞百分比相乘,乘积≥4分为高表达, < 4分为低表达[12-13]

    将U87细胞株置于10%胎牛血清、高糖DMEM液体培养液,37℃、5%CO2及饱和湿度条件下培养,每3~5天用胰酶消化传代1次,取对数生长期细胞进行实验。

    于6孔板内接种对数生长期U87细胞,细胞密度为2×105个每孔,培养液为不含抗生素的DMEM培养液。待细胞生长至60%~80%融合度时,更换为不含血清的DMEM培养液,12 h后按转染试剂RNAi MAX转染方法将MKK4-siRNA、MKK7-siRNA1、MKK7-siRNA2和空白对照siRNA分别转染入U87细胞。

    U87转染细胞于37℃培养箱培养48 h后,每孔2 ml PBS漂洗2遍,每孔加入150 μl IP细胞裂解液(50 mmol/L Tris, HCl pH8.0, 150 mmol/L NaCl, 1%Triton×100, 100 μg/ml PMSF),10 min后收集各组细胞。按照IP裂解液法提取细胞总蛋白,并进行BCA法测定蛋白浓度。灌制4%集成胶和10%分离胶。200 V电压电泳45 min。100 V电压转膜60 min。5%脱脂奶粉室温封闭1 h。一抗(anti-MKK4 1:1 000,anti-MKK7 1:1 000,anti-c-Jun 1:1 000,anti-p-c-Jun 1:1 000,anti-GAPDH 1:5 000)4℃孵育过夜,HRP标记抗兔或抗鼠室温孵育1 h。ECL化学发光后曝光。

    用SPSS20.0统计分析软件包进行数据处理。多组间MKK7及p-c-Jun表达率的比较用多个样本率的χ2检验。数据以平均值±标准差(x±s)表示,多样本间比较采用单因素方差分析One-way ANOVA,两组间的比较采用独立样本t检验。相关性分析采用Spearman等级相关分析。P < 0.05为差异有统计学意义。

    c-Jun和p-c-Jun阳性表达表现为细胞核内见棕黄色颗粒,见图 1。25例胶质母细胞瘤中3例(12%)c-Jun高表达,其瘤旁正常脑组织中均低表达,两者间差异无统计学意义(χ2=3.128, P=0.077),而胶质母细胞瘤中p-c-Jun高表达19例(76%),明显高于瘤旁正常脑组织6例(4%),差异有统计学意义(χ2=27.000, P=0.000)。胶质母细胞瘤中c-Jun的表达与其他类型胶质瘤无明显差异(P=0.086),但p-c-Jun表达明显升高(P=0.000),见表 2。根据WHO分级,WHO Ⅳ级胶质瘤p-c-Jun高表达率明显高于WHO Ⅱ级及WHO Ⅲ级胶质瘤(P=0.000),见图 2A,且p-c-Jun表达强度与胶质瘤WHO分级呈明显正相关(r=0.494, P=0.000)。

    图  1  不同WHO分级胶质瘤及胶质母细胞瘤瘤旁正常脑组织中c-Jun、p-c-Jun、MKK7的表达
    Figure  1  Expression of c-Jun, p-c-Jun and MKK7 in gliomas with different WHO classification and normal brain tissues adjacent to glioblastoma
    A-D: c-Jun, p-c-Jun and MKK7 expression in normal brain tissues adjacent to glioblastoma; E-H: oligodendroglioma(WHO Ⅱ); I-L: anaplastic astrocytoma(WHO Ⅲ); M-P: glioblastoma (WHO Ⅳ); A, E, I, M: HE×200; B-D, F-H, J-L, N-P: IHC ×200
    表  2  不同组织学类型胶质瘤组织中c-Jun及p-c-Jun表达情况
    Table  2  c-Jun and p-c-Jun expression in different histological types of gliomas
    下载: 导出CSV 
    | 显示表格
    图  2  MKK7及p-c-Jun在胶质瘤中的表达相关性分析
    Figure  2  Correlation of MKK7 and p-c-Jun expression in gliomas
    1: normal brain tissue adjacent to GBM; 2: WHOⅡ; 3: WHOⅢ; 4: WHOⅣ

    MKK7阳性表达表现为细胞核或质内见棕黄色颗粒,见图 1。胶质母细胞瘤中MKK7的表达高于其他类型胶质瘤及胶质母细胞瘤瘤旁正常脑组织(P=0.000),见表 3。且MKK7高表达率随着WHO分级的升高而增加(P=0.000),见图 2A。MKK7表达强度与胶质瘤WHO分级呈明显正相关(r=0.606, P=0.000)。

    表  3  不同组织学类型胶质瘤及胶质母细胞瘤瘤旁正常脑组织组织中MKK7表达情况
    Table  3  MKK7 expression in gliomas with different histological types and normal brain tissues adjacent to glioblastoma
    下载: 导出CSV 
    | 显示表格

    92例胶质瘤及25例胶质瘤母细胞瘤瘤旁正常脑组织中,48例MKK7和p-c-Jun均高表达,31例均低表达,30例MKK7高表达和p-c-Jun低表达,8例MKK7低表达和p-c-Jun高表达。根据Spearman相关分析检验,MKK7表达与c-Jun磷酸化水平正相关(r=0.387, P=0.000),见图 2B

    与空白对照组siRNA相比,U87细胞转染MKK4-siRNA、MKK7-siRNA1和MKK7-siRNA2可分别显著抑制MKK4(P=0.003)和MKK7(P=0.009)表达,但只有转染MKK7-siRNA可同时下调c-Jun磷酸化水平(P=0.004),见图 3

    图  3  U87细胞株小分子干扰对MKK4、MKK7的表达及对c-Jun活性的影响
    Figure  3  Effects of siRNAs on MKK4, MKK7 expression and c-Jun activities in glioma U87 cell line analyzed by Western blot
    *: P < 0.05, compared with NC-siRNA groups

    c-Jun N-末端激酶(C-Jun N-terminal kinase, JNK)属于丝裂原活化蛋白激酶家族,其家族包括JNK1、JNK2和JNK3[14],其中JNK1和JNK2广泛表达于各种组织中,而JNK3主要表达于脑、心脏及睾丸等组织中[15]。JNKs参与许多生理过程,如炎性反应、细胞增殖、分化及死亡,Nacken等[16]研究表明JNK活化可促进流感病毒A(IAV)的非结构蛋白(NS1)的表达,从而诱导细胞的凋亡。而且肿瘤的发生和进展也存在JNKs的持续激活,有研究通过体内或体外实验证明多种恶性肿瘤与JNK/c-Jun的激活密切相关,如胃癌、肝癌、胰腺癌、骨肉瘤、脑肿瘤及结直肠癌等中均存在不同JNK蛋白的高表达或突变[17-20]。本研究基于免疫组织化学方法,探讨胶质瘤中c-Jun的磷酸化水平的表达情况。与正常脑组织及非胶质母细胞瘤相比,胶质母细胞瘤中磷酸化c-Jun的表达明显升高,胶质母细胞瘤的高表达率为81.1%,表明磷酸化c-Jun过表达参与了胶质母细胞瘤的发生与发展。

    替莫唑胺(TMZ)是目前公认的治疗脑胶质瘤效果较好的化疗药物,然而脑胶质瘤对TMZ产生耐药性是导致化疗失败的重要原因。因此,为胶质母细胞瘤的化疗寻找新的靶点及新的化疗药物成为了胶质瘤的研究热点。有研究证明在JNK/c-Jun激活后,可以增强替莫唑胺和尼莫司汀等烷化剂等药物对胶质母细胞瘤的促凋亡作用。Tomicic等[21]发现烷基化抗癌药物作用于胶质瘤细胞LN-229后,JNK/c-Jun激活参与了晚期促凋亡反应。Ueno等[22]通过建立耐TMZ细胞模型,与对照组相比,试验组c-Jun终末激酶(JNK)的磷酸化水平增加,其下游信号通路的活性增加。上调JNK表达或siRNA特异性干扰及JNK抑制剂抑制JNK表达可以促进或抑制试验组细胞迁移及侵袭。因此,表明JNK信号通路可能成为新型治疗TMZ耐药胶质瘤的靶点。本研究也进一步证明不同级别胶质瘤c-Jun的表达水平不同,为胶质瘤的化疗,特别是TMZ耐药的处理提供了证据。

    JNK/c-Jun通路的激活在胶质母细胞瘤的发生发展过程中起重要作用,但其上游调控机制并不完全清楚。JNK上游有两个MAPKK,即MKK4和MKK7。我们通过小分子干扰的方法沉默胶质瘤U87细胞株中MKK4及MKK7,发现沉默MKK7后c-Jun磷酸化水平明显下调,而沉默MKK4后c-Jun磷酸化水平无明显变化,在细胞学水平证明了MKK7是调控JNK/c-Jun活性及胶质瘤细胞增殖的关键分子。为了进一步探讨MKK7和磷酸化c-Jun的表达在胶质瘤发生发展中的关系。本研究检测了胶质母细胞瘤瘤旁正常脑组织与不同组织学类型及WHO分级的胶质瘤中MKK7和磷酸化c-Jun的表达情况,发现随着胶质瘤WHO分级的增加,MKK7及磷酸化c-Jun的高表达率明显升高;且MKK7及磷酸化c-Jun的表达正相关,进一步验证了MKK7及JNK/c-Jun通路的信号在胶质母细胞瘤发生发展的中的重要作用,为寻找胶质瘤化疗的新靶点、新化疗药物提供重要的理论依据。

    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
  • [1]

    Arnold M, Sierra MS, Laversanne M, et al. Global patterns and trends in colorectal cancer incidence and mortality[J]. Gut, 2017, 66(4): 683-691. doi: 10.1136/gutjnl-2015-310912

    [2]

    Lee YC, Lee YL, Chuang JP, et al. Differences in survival between colon and rectal cancer from SEER data[J]. PLoS One, 2013, 8(11): e78709. doi: 10.1371/journal.pone.0078709

    [3]

    Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review[J]. JAMA, 2021, 325(7): 669-685. doi: 10.1001/jama.2021.0106

    [4]

    Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody[J]. Clin Cancer Res, 2013, 19(2): 462-468. doi: 10.1158/1078-0432.CCR-12-2625

    [5]

    Wagner M, Jasek M, Karabon L. Immune Checkpoint Molecules-Inherited Variations as Markers for Cancer Risk[J]. Front Immunol, 2021, 11: 606721. doi: 10.3389/fimmu.2020.606721

    [6]

    Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations[J]. Sci Transl Med, 2016, 8(328): 328rv4.

    [7]

    Mortezaee K, Najafi M. Immune system in cancer radiotherapy: Resistance mechanisms and therapy perspectives[J]. Crit Rev Oncol Hematol, 2021, 157: 103180. doi: 10.1016/j.critrevonc.2020.103180

    [8]

    Liu J, Chen Z, Li Y, et al. PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy[J]. Front Pharmacol, 2021, 12: 731798. doi: 10.3389/fphar.2021.731798

    [9]

    Majidpoor J, Mortezaee K. The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives[J]. Clin Immunol, 2021, 226: 108707. doi: 10.1016/j.clim.2021.108707

    [10]

    Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer[J]. Am J Cancer Res, 2020, 10(3): 727-742.

    [11]

    Wojtukiewicz MZ, Rek MM, Karpowicz K, et al. Inhibitors of immune checkpoints-PD-1, PD-L1, CTLA-4-new opportunities for cancer patients and a new challenge for internists and general practitioners[J]. Cancer Metastasis Rev, 2021, 40(3): 949-982. doi: 10.1007/s10555-021-09976-0

    [12]

    Yan Y, Zhang L, Zuo Y, et al. Immune Checkpoint Blockade in Cancer Immunotherapy: Mechanisms, Clinical Outcomes, and Safety Profiles of PD-1/PD-L1 Inhibitors[J]. Arch Immunol Ther Exp (Warsz), 2020, 68(6): 36. doi: 10.1007/s00005-020-00601-6

    [13]

    Zhou Q, Xiao H, Liu Y, et al. Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization[J]. J Immunol, 2010, 185(9): 5082-5092. doi: 10.4049/jimmunol.1001821

    [14]

    Sgambato A, Casaluce F, Sacco PC, et al. Anti PD-1 and PDL-1 Immunotherapy in the Treatment of Advanced Non- Small Cell Lung Cancer (NSCLC): A Review on Toxicity Profile and its Management[J]. Curr Drug Saf, 2016, 11(1): 62-68. doi: 10.2174/1574886311207040289

    [15]

    Jenkins MA, Hayashi S, O'Shea AM, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study[J]. Gastroenterology, 2007, 133(1): 48-56. doi: 10.1053/j.gastro.2007.04.044

    [16]

    Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study[J]. Lancet Oncol, 2017, 18(9): 1182-1191. doi: 10.1016/S1470-2045(17)30422-9

    [17]

    Overman MJ, Lonardi S, Wong KYM, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer[J]. J Clin Oncol, 2018, 36(8): 773-779. doi: 10.1200/JCO.2017.76.9901

    [18]

    Le DT, Kim TW, Van Cutsem E, et al. PhaseⅡ Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164[J]. J Clin Oncol, 2020, 38(1): 11-19. doi: 10.1200/JCO.19.02107

    [19]

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer[J]. N Engl J Med, 2020, 383(23): 2207-2218. doi: 10.1056/NEJMoa2017699

    [20]

    Andre T, Amonkar M, Norquist JM, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial[J]. Lancet Oncol, 2021, 22(5): 665-677. doi: 10.1016/S1470-2045(21)00064-4

    [21]

    Montalban-Arques A, Scharl M. Intestinal microbiota and colorectal carcinoma: Implications for pathogenesis, diagnosis, and therapy[J]. EBioMedicine, 2019, 48: 648-655. doi: 10.1016/j.ebiom.2019.09.050

    [22]

    Cheng Y, Ling Z, Li L. The Intestinal Microbiota and Colorectal Cancer[J]. Front Immunol, 2020, 11: 615056. doi: 10.3389/fimmu.2020.615056

    [23]

    Wong SH, Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(11): 690-704. doi: 10.1038/s41575-019-0209-8

    [24]

    Yang Y, Weng W, Peng J, et al. Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor-κB, and Up-regulating Expression of MicroRNA-21[J]. Gastroenterology, 2017, 152(4): 851-866. doi: 10.1053/j.gastro.2016.11.018

    [25]

    Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, et al. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer[J]. Int J Mol Sci, 2017, 18(1): 197. doi: 10.3390/ijms18010197

    [26]

    Yang Y, Misra BB, Liang L, et al. Integrated microbiome and metabolome analysis reveals a novel interplay between commensal bacteria and metabolites in colorectal cancer[J]. Theranostics, 2019, 9(14): 4101-4114. doi: 10.7150/thno.35186

    [27]

    Zhang SL, Mao YQ, Zhang ZY, et al. Pectin supplement significantly enhanced the anti-PD-1 efficacy in tumor-bearing mice humanized with gut microbiota from patients with colorectal cancer[J]. Theranostics, 2021, 11(9): 4155-4170. doi: 10.7150/thno.54476

    [28]

    Zhang SL, Han B, Mao YQ, et al. Lacticaseibacillus paracasei sh2020 induced antitumor immunity and synergized with anti-programmed cell death 1 to reduce tumor burden in mice[J]. Gut Microbes, 2022, 14(1): 2046246. doi: 10.1080/19490976.2022.2046246

    [29]

    Peng Z, Cheng S, Kou Y, et al. The Gut Microbiome Is Associated with Clinical Response to Anti-PD-1/PD-L1 Immunotherapy in Gastrointestinal Cancer[J]. Cancer Immunol Res, 2020, 8(10): 1251-1261. doi: 10.1158/2326-6066.CIR-19-1014

    [30] 徐新建. 肠道菌群通过代谢途径影响PD-1抑制剂治疗结直肠癌疗效的研究[D]. 石家庄: 河北医科大学, 2020.

    Xu XJ, Gut Flora Influences the Efficacy of PD-1 Inhibitor on the Treatment of Colorectal Cancer via Metabolic Pathway[D]. Shijiazhuang: Hebei Medical University, 2020.

    [31]

    Xu X, Lv J, Guo F, et al. Gut Microbiome Influences the Efficacy of PD-1 Antibody Immunotherapy on MSS-Type Colorectal Cancer via Metabolic Pathway[J]. Front Microbiol, 2020, 11: 814. doi: 10.3389/fmicb.2020.00814

    [32]

    Yoon Y, Kim G, Jeon BN, et al. Bifidobacterium Strain-Specific Enhances the Efficacy of Cancer Therapeutics in Tumor-Bearing Mice[J]. Cancers (Basel), 2021, 13(5): 957. doi: 10.3390/cancers13050957

    [33]

    Mager LF, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy[J]. Science, 2020, 369(6510): 1481-1489. doi: 10.1126/science.abc3421

    [34]

    Copur MS. Immunotherapy in Colorectal Cancer[J]. Oncology(Williston Park), 2019, 33(10): 686506.

    [35]

    Montalban-Arques A, Katkeviciute E, Busenhart P, et al. Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors[J]. Cell Host Microbe, 2021, 29(10): 1573-1588. doi: 10.1016/j.chom.2021.08.001

    [36]

    Tanoue T, Morita S, Plichta DR, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity[J]. Nature, 2019, 565(7741): 600-605. doi: 10.1038/s41586-019-0878-z

    [37]

    Song W, Tiruthani K, Wang Y, et al. Trapping of Lipopolysaccharide to Promote Immunotherapy against Colorectal Cancer and Attenuate Liver Metastasis[J]. Adv Mater, 2018, 30(52): e1805007. doi: 10.1002/adma.201805007

    [38]

    Lv J, Jia Y, Li J, et al. Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment[J]. Cell Death Dis, 2019, 10(6): 415. doi: 10.1038/s41419-019-1638-6

    [39]

    Oh B, Boyle F, Pavlakis N, et al. The Gut Microbiome and Cancer Immunotherapy: Can We Use the Gut Microbiome as a Predictive Biomarker for Clinical Response in Cancer Immunotherapy?[J]. Cancers (Basel), 2021, 13(19): 4824. doi: 10.3390/cancers13194824

    [40]

    Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J]. Science, 2018, 359(6371): 91-97. doi: 10.1126/science.aan3706

    [41]

    Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients[J]. Science, 2018, 359(6371): 104-108. doi: 10.1126/science.aao3290

    [42]

    Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota[J]. Science, 2015, 350(6264): 1079-1084. doi: 10.1126/science.aad1329

    [43]

    Oster P, Vaillant L, Riva E, et al. Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies[J]. Gut, 2022, 71(3): 457-466. doi: 10.1136/gutjnl-2020-323392

    [44]

    Mao J, Wang D, Long J, et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers[J]. J Immunother Cancer, 2021, 9(12): e003334. doi: 10.1136/jitc-2021-003334

计量
  • 文章访问数:  1450
  • HTML全文浏览量:  430
  • PDF下载量:  1076
  • 被引次数: 0
出版历程
  • 收稿日期:  2022-04-21
  • 修回日期:  2022-08-22
  • 网络出版日期:  2024-01-12
  • 刊出日期:  2022-11-24

目录

/

返回文章
返回
x 关闭 永久关闭