Non-alcoholic Fatty Liver Disease Affect Efficacy of Immune Checkpoint Inhibitors for Patients with Hepatocellular Carcinoma: Manifestations and Mechanisms
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摘要:
近年来,非酒精性脂肪肝合并肝细胞癌的患者数量逐渐上升,免疫治疗在晚期肝细胞癌的治疗中扮演着越来越重要的角色。既往研究发现非酒精性脂肪肝可以影响肝细胞癌免疫治疗的疗效,但机制不清,可能与这些因素相关:非酒精性脂肪肝中CD8+PD-1+T细胞增多导致肝脏细胞增殖能力缺陷;锌指蛋白64激活CSF1抑制抗肿瘤免疫;PCSK9下调LDLR水平抑制肿瘤微环境中CD8+T细胞免疫应答;免疫应答的缺失导致肝损伤等。研究发现联合使用仑伐替尼、PKCa抑制剂、PCSK9蛋白的抑制、铁死亡诱导剂、HIF2a小分子抑制剂可以改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂的疗效。本文就非酒精性脂肪肝对肝脏免疫微环境和肝细胞癌免疫检查点抑制剂疗效的影响和机制,以及如何改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂疗效的研究进行综述。
Abstract:The number of patients with the combination of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) is gradually increasing. In recent years, the immunotherapy has become a new effective way to treat unresectable HCC. The clinical research revealed that the NAFLD could affect the efficacy of immunotherapy treating the HCC. But the mechanism is complicated. The major routes are CD8+PD-1+T cells increasing in NAFLD cause the deficiency in cell proliferation ability; Zn64 activates the anti-tumor immune response of the CSF1; PCSK9 downregulates the LDLR level to suppress the immune response of the CD8+T cells in tumor microenvironment; loss of the immune response induces the liver damage. Researches had indicated that the combination of lenvatinib, PKCa inhibitor, PCSK9 protein inhibition, ferroptosis inducer, and HIF2a small molecule inhibitor can improve the efficacy of immune checkpoint inhibitors for NAFLD-associated hepatocellular carcinoma. This review focuses on the impact of NAFLD on tumor microenvironment and how the NAFLD affect the immune check-point inhibitor effect and to discover the exact mechanism.
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0 引言
2020年全球最新癌症报告显示原发性肝癌在全球范围内的发病率和死亡率分别排名第六位和第三位,死亡例数接近新发病例数[1]。在中国,原发性肝癌新发病例数约占全球的50%,是目前我国第2位肿瘤致死病因,严重威胁着人们的生命健康和生活质量[2]。肝细胞肝癌(hepatocellular carcinoma, HCC)是原发性肝癌最常见的病理学类型,占85%~90%[3]。
目前,手术切除和肝移植是肝癌治疗的首选,也是最有效的方法,完全缓解率高,平均5年生存率高达40%~70%,而晚期HCC患者的中位生存期小于1年[4],多数患者诊断时已达晚期,并伴有肝硬化,有机会接受手术的患者不足40%[5]。这也提示肝癌的早期诊断率低、治疗和预后相对较差。由于存在针道肿瘤扩散和出血的风险,HCC诊断通常是基于影像学而不是活检[6],动态增强CT和多模态MRI扫描是肝脏超声和血清AFP筛查异常者明确诊断的首选影像学检查方法。但传统影像学方法仅能提供形态学信息,不能提供相关生物学信息,因此在预测肿瘤复发风险方面缺乏准确性。
正电子发射显像(positron emission tomography, PET)是利用发射正电子的放射性核素(如18F、11C、68Ga等)在分子生物学水平对肿瘤代谢及微环境进行探测的功能分子影像技术,与反应解剖信息的计算机断层显像(computed tomography, CT)技术相结合,能同时反应肿瘤病变的生物学和形态学信息。PET/CT是一种无创、全身性的检查,一次检查可显示全身肿瘤病灶,因此,已广泛应用于多种肿瘤的早期诊断、临床分期、疗效评估及预后等方面[7]。
18氟-氟代脱氧葡萄糖(fluor-18-deoxy-glucose, 18F-FDG)是目前临床上最常用的PET显像剂。肿瘤细胞的葡萄糖代谢旺盛,18F-FDG与天然葡萄糖结构相似,因此,可以被葡萄糖转运体转入细胞,在己糖激酶的作用下生成6-磷酸-18F-FDG,因其无法继续参与肿瘤糖代谢,因此滞留于肿瘤细胞内,影像学上表现为异常显像剂浓聚。临床通常采用标准摄取值(standardized uptake value, SUV)对18F-FDG的浓聚程度进行定量分析,低分化的HCC恶性程度高,SUV值也高;分化良好的HCC,SUV值接近正常肝脏[8]。目前,18F-FDG PET/CT已广泛应用于多种肿瘤的早期诊断、分期、疗效评估及预后等方面,本文旨在对18F-FDG PET/CT在HCC诊断、肝移植术、切除术及局部消融术中的应用进展进行更新和述评,为临床合理应用18F-FDG PET/CT进行HCC的精准诊疗提供参考。
1 PET/CT在HCC诊断中的应用
此前,已有较多的临床研究显示,18F-FDG PET诊断原发性HCC的敏感度较低,在50%左右,但在中低分化肝癌诊断中的检出率达75%,且在转移性肝癌病灶中18F-FDG摄取明显较高[9-13]。最近,Celebi等分析了39例肝内胆管癌/MRI与原发性肝内肿块形成的组织病理分型和组织学分级的关系,发现18F-FDG区分HCC和肝内胆管癌的敏感度为86.7%,特异性为67%,SUV值在低分化和中高分化HCC中有显著差异,因此,18F-FDG PET/CT显像有助于预测肝内原发肿瘤的类型及HCC的分级[14]。目前研究认为,高分化原发性HCC 18F-FDG的低摄取是基于其本身的分子生物学特点,高分化的HCC细胞中葡萄糖-6-磷酸酶高表达,与正常肝脏细胞接近,导致6-磷酸-18F-FDG被还原为18F-FDG后排出肿瘤细胞,显像剂浓聚程度接近正常肝脏[15]。因此,18F-FDG PET/CT通常作为常规检查的补充方法,美国国立综合癌症网络(National Comprehensive Cancer Network, NCCN)指南中也明确指出18F-FDG PET/CT目前不推荐作为HCC临床诊断的常规手段。虽然18F-FDG PET/CT在原发性HCC诊断中的应用有限,但在检测肝外转移和复发时敏感度较高,肝外转移的检测对确定理想的治疗方案至关重要,可以减少不必要的手术治疗。Lee等报道18F-FDG PET/CT在 > 1 cm的肝外转移检出率高达92.3%[16],在移植后HCC复发的患者中检出率达90%[17]。2019年Refaat等进行的前瞻性研究纳入了100例等待肝移植过程中接受桥接治疗后甲胎蛋白(alpha-fetoprotein, AFP)升高的HCC患者,使用18F-FDG PET/CT增强显像的方法检测患者的病灶转移及复发,其敏感度、特异性和准确性均较高,分别为92.8%、94.1%和93%[18]。因此,许多专家学者也建议将18F-FDG PET/CT纳入AFP升高等具有较大转移和复发风险的HCC临床常规诊断中。
为弥补18F-FDG对高分化HCC诊断的缺陷,一些新的PET示踪剂,如11C-胆碱、18F-胆碱、11C-乙酸盐等已被报道可以显著提高HCC诊断的敏感度,尤其是与18F-FDG联合使用[19]。胆碱以参与磷脂合成用于肿瘤代谢显像,乙酸盐以参与脂肪酸合成而被肿瘤摄取,有研究表明11C-胆碱和11C-乙酸盐对高分化HCC的诊断敏感度均显著高于18F-FDG,但在低分化HCC诊断敏感度则不如18F-FDG[20-22],当与18F-FDG联合显像可显著提高肝癌的检出率,诊断敏感度可达90%以上[13, 23-24]。有文献报道,在肝癌多学科会诊中纳入11C-胆碱显像结果可以影响10%~30%肝癌患者的诊断、分期和临床治疗方案的选择[13, 25-26]。近两年,68Ga或18F标记的-PSMA对HCC的诊断研究日趋增多[9, 27-28]。前列腺特异性膜抗原(PSMA)是一种Ⅱ型跨膜糖蛋白,除了在前列腺癌中高表达,在其他多种肿瘤的的新生血管中也高度表达。大多数HCC在肿瘤血管和细胞小管膜上显示PSMA高表达[29-30]。目前,68Ga-PSMA PET临床研究多为单中心小样本量研究,初步临床研究结果显示68Ga-PSMA相对于18F-FDG能检测到更多的病变组织[31-33],在HCC分期方面优于18F-FDG[9]。成纤维细胞激活蛋白(fibroblast activation protein, FAP)存在于多种恶性上皮性肿瘤的间质。最近,靶向FAP蛋白的显像剂68Ga-FAPI-04已经被用于多种肿瘤的PET成像[34],但在HCC诊断方面的临床研究较少,Shi等报道的16例患者的28处肝内病变均呈现68Ga-FAPI-04的摄取增高,病理结果显示均为恶性病变,68Ga-FAPI-04 PET/CT对肝内恶性肿瘤的检测敏感度为100%[28]。Wang等对29例HCC患者同时进行18F-FDG和68Ga-FAPI-04 PET/CT显像发现,68Ga-FAPI-04检测肝内HCC病变的敏感度显著高于18F-FDG(85.7% vs. 57.1%),尤其是对于中、高分化和直径小于2 cm的HCC病灶表现更为突出,有望成为一种有前途的HCC诊断显像剂[35]。未来还需要进一步的大样本研究和前瞻性的临床试验来阐明靶向PSMA和FAP的新型示踪剂在该领域的临床诊断作用。
2 18F-FDG PET/CT在HCC肝移植治疗中的应用
肝移植术是HCC根治性治疗的最有效方法,尤其适用于肝功能失代偿或不适合手术切除的早期肝癌患者。为了提高肝癌移植疗效、保证宝贵的肝脏资源能得到公平合理的使用,肝移植术有非常严格的适应证。目前国际上应用最广泛的有米兰标准和加州大学旧金山分校标准(UCSF)等[36],国内尚无统一的标准。根据临床实践经验,我国学者也提出了杭州标准、上海复旦标准、华西标准等,相比于米兰标准,均不同程度扩大了肝移植的使用范围,从而使更多的患者受益[37-38]。遵循这些标准,可以显著改善肝癌患者的治疗结果,肝移植后的5年平均生存率达60%~80%。目前,临床使用的肝移植标准多依赖于形态学影像参数所估计的肿瘤负荷(肿瘤的大小和数量等),并未纳入肿瘤生物学相关因素,如肿瘤分化、分子标志物及桥接治疗反应等,肿瘤复发引起的肝移植失败率达15%~20%[39]。
越来越多的研究表明,18F-FDG PET/CT可以独立预测肝移植患者的肿瘤复发,并在肿瘤生物学行为和肝移植预后等方面提供更多的信息[40-41]。一项包括182例肝移植患者的多中心研究发现,23例HCC患者术后复发,而18F-FDGPET阳性是复发的重要独立危险因素,阳性患者5年内复发率明显高于阴性患者(28% vs. 12%)[40]。Kornberg等的研究也发现接受肝移植治疗的HCC患者中,PET/CT阴性患者与阳性患者的5年无病生存率分别为93.3%和38.1%,PET/CT阳性组复发率为58.5%,而PET/CT阴性患者复发率仅为6.7%[42]。对移植前进行18F-FDG PET/CT显像的肝移植患者数据进行分析发现,PET/CT检查结果与肿瘤大小、数量、分期、微血管侵犯和组织学确定的米兰标准之间存在相关性[43-44],高级别肿瘤患者和发生微血管侵犯的患者中PET/CT阳性率分别为83.3%和82.3%,PET阴性患者的3年无复发生存率为93%,而PET阳性人群仅为35%。
一项包含147例接受肝移植的HCC患者临床数据显示,UCSF标准内的患者与超过UCSF标准且18F-FDG低摄取的患者移植后复发率相近[45]。韩国一项研究纳入的患者有一半超过米兰标准,其PET/CT阴性患者的5年无病生存率达73%[46]。一项包含116例以Up-to-seven(UTS)放射学为移植标准的临床研究发现,UTS标准以内的患者18F-FDG PET阴性患者的5年无复发生存率(94.9%)远高于PET阳性患者(48.3%),而且标准以外,18F-FDG PET阴性患者5年无复发生存率(87.1%)远高于PET阳性患者(19%)[43]。2013年,Lee等发表了一项包含191例肝移植患者的回顾性研究,该研究中超过30%的肝移植患者超过米兰标准,结果显示,无病生存率为80.1%,早期复发患者中75%为PET/CT阳性。PET/CT阳性患者的3年总生存率和无病生存率(65.5%, 57.1%)均显著低于PET/CT阴性组(89.9%, 86.8%),且与肿瘤分级、术前AFP水平、肿瘤微血管侵犯和大血管侵犯密切相关[47]。
18F-FDG PET/CT可以反映肿瘤代谢生物学信息及形态学信息,与临床常用的肝移植候选标准既有相关性,又有不可替代的补充作用。由于可供移植的器官稀缺,仔细选择肝移植患者对于确保良好的结果至关重要。因此,18F-FDG PET/CT可以为预测肝癌的预后和选择肝移植的最佳候选者提供重要信息。近年来,越来越多的专家学者提出将PET/CT推广到肝移植候选的HCC患者中,对不符合米兰等标准且PET阴性的患者,可以适当放宽适应证,从而使更多的患者受益,而对于符合米兰等标准但PET阳性的患者应结合其他生物学指标重点考虑是否有必要进行更昂贵或放弃无效的治疗。
3 18F-FDG PET/CT在HCC手术及局部消融术预后评估中的应用
肝癌切除术是肝癌患者获得长期生存的重要手段,手术切除的首选适应证较多地依赖于传统影像学的形态学表现进行分期,但切除术后5年肿瘤复发转移率高达40%~70%。这与术前可能已存在微小播散灶或多中心发生,以及微血管侵犯等有关。18F-FDG可以反应肿瘤的代谢活性,与肿瘤恶性程度、侵袭性、转移及复发显著相关[40]。术前18F-FDG PET/CT有助于提高对肿瘤生物侵袭性的评估,为新辅助治疗提供参考,而从降低肝癌切除术后的高复发率。Lim等进行的一项回顾性研究发现,18F-FDG PET阳性是肿瘤微血管侵犯的唯一独立预测因子,特异性和敏感度分别为73%和62%[48]。Sun等进行的一项包含22项研究1 721例患者的Meta分析显示,肿瘤对18F-FDG的高摄取与总生存期和5年无病生存期降低显著相关[49]。
局部消融治疗对不适合手术切除的肝癌患者可显著提高生存率。研究显示,术前18F-FDG摄取程度与术后反应(CT显示肿瘤体积缩小30%及以上)相关,以肿瘤最大SUV值与肝脏平均SUV值大于1.9为PET阳性标准,发现PET阴性患者中77%对局部消融治疗反应良好,而PET阳性组仅有23%。多变量因素分析发现,18F-FDG摄取是预测治疗反应的唯一显著因素,随访结果也显示PET阴性与患者五年生存率显著相关[50]。另一项研究,以肿瘤最大SUV值与肝脏平均SUV值1.7为PET阳性和阴性界值,PET阴性组和阳性组对局部消融治疗的应答率分别为81.2%和50%,中位生存期分别为16.8月和8.1月[51]。
18F-FDG PET/CT在术前HCC的初始检查中并不常规使用,但鉴于其在预后中的独特作用,未来18F-FDG PET/CT有望改变HCC患者的分期,改善手术适应证,从而降低术后的复发率,提高患者生存率。
4 问题和展望
肿瘤诊疗领域,积极倡导多学科诊疗团队(multidisciplinary team, MDT)的模式,特别是对疑难复杂病例的诊治,发挥各学科优势,促进学科交流,实现肿瘤的精准诊疗。目前临床上,肝癌的各种影像学检查手段各有特点,应该强调综合应用、优势互补。超声检查因操作简便、实时无创、移动便捷等特点,是临床上最常用的肝脏影像学检查方法。动态增强CT和多模态MRI扫描是肝脏超声和血清AFP筛查异常者明确诊断的首选影像学检查方法。肝脏多模态MRI具有无辐射影响、组织分辨率高、可多方位多序列参数成像的优势,加上特异性对比剂,可提高肝癌微小病灶的检出率以及对肝癌诊断与鉴别诊断的准确性。这些传统影像学检查方法具有简便、快捷、辐射低等优势,但都是反映肿瘤的形态学信息,缺乏生物学信息,而肿瘤的生物学行为更能在早期反映肿瘤的恶性程度、治疗预后。
相对于传统影像学方法显示的形态学信息,PET/CT整合了PET功能代谢与CT解剖学信息的优势,可以在一次显像中获得全身的肝外转移灶、治疗后早期复发转移灶、评估疗效及预后、指导生物靶区的勾画及确定活检部位等。越来越多的临床研究显示出18F-FDG PET/CT作为肿瘤体内影像学生物标志物在指导HCC临床诊疗中的重要作用,尤其是在肝移植术前评估、术后预后等方面具有不可替代的作用。虽然18F-FDG PET/CT对HCC的诊断率较低,限制了其在HCC临床常规诊断中的应用,但可以作为其他检查的辅助手段。近年来新的显像剂不断涌现,在HCC诊断中表现出较高的敏感度,尤其是双示踪剂的应用,极大提高了PET显像技术诊断HCC的敏感度。但考虑到目前全国核医学科及核医学设备的数量、核素半衰期、双示踪剂显像的累积辐射剂量及成本效益等问题,PET/CT显像技术在原发性HCC诊断中的增益价值有待进一步评估。随着核医学“一县一科”项目的推进、未来PET检查技术的普及,相信未来PET显像一定会与传统影像学诊断技术及肿瘤生物学标志物相结合,在肝癌的精准诊疗中发挥举足轻重的作用。
Competing interests: The authors declare that they have no competing interests.作者贡献:袁野:文献检索及论文写作彭慧:文章修改田德安:提出文章思路,指导及审核论文 -
[1] McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma[J]. Hepatology, 2021, 73 Suppl 1(Suppl 1): 4-13.
[2] 中华人民共和国国家卫生健康委员会. 原发性肝癌诊疗指南(2022年版)[J]. 肿瘤防治研究, 2022, 49(3): 251-276. doi: 10.3971/j.issn.1000-8578.2022.03.0001 National Health Commission of the People's Republic of China. Standardization for Diagnosis and Treatment of Primary Hepatic Carcinoma (2022 Edition)[J]. Zhong Liu Fang Zhi Yan Jiu, 2022, 49(3): 251-276. doi: 10.3971/j.issn.1000-8578.2022.03.0001
[3] Vogel A, Martinelli E. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines[J]. Ann Oncol, 2021, 32(6): 801-805. doi: 10.1016/j.annonc.2021.02.014
[4] Nan Y, An J, Bao J, et al. The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease[J]. J Hepatol, 2021, 75(2): 454-461. doi: 10.1016/j.jhep.2021.05.003
[5] Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases[J]. Aliment Pharmacol Ther, 2018, 48(7): 696-703. doi: 10.1111/apt.14937
[6] Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies[J]. Nat Med, 2018, 24(7): 908-922. doi: 10.1038/s41591-018-0104-9
[7] Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease[J]. J Clin Invest, 2005, 115(5): 1343-1351. doi: 10.1172/JCI23621
[8] Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study[J]. Hepatology, 2016, 63(3): 827-838. doi: 10.1002/hep.28368
[9] Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis[J]. Nature, 2016, 531(7593): 253-257. doi: 10.1038/nature16969
[10] Feldstein AE, Lopez R, Tamimi TA, et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. J Lipid Res, 2010, 51(10): 3046-3054. doi: 10.1194/jlr.M007096
[11] Ma X, Bi E, Huang C, et al. Cholesterol negatively regulates IL-9-producing CD8(+) T cell differentiation and antitumor activity[J]. J Exp Med, 2018, 215(6): 1555-1569. doi: 10.1084/jem.20171576
[12] Dudek M, Pfister D, Donakonda S, et al. Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH[J]. Nature, 2021, 592(7854): 444-449. doi: 10.1038/s41586-021-03233-8
[13] Li X, Ramadori P, Pfister D, et al. The immunological and metabolic landscape in primary and metastatic liver cancer[J]. Nat Rev Cancer, 2021, 21(9): 541-557. doi: 10.1038/s41568-021-00383-9
[14] Xu CF, Yu CH, Li YM, et al. Association of the frequency of peripheral natural killer T cells with nonalcoholic fatty liver disease[J]. World J Gastroenterol, 2007, 13(33): 4504-4508. doi: 10.3748/wjg.v13.i33.4504
[15] Huang C, Mulla S, Wang Y, et al. IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma[J]. N Engl J Med, 2020, 382(20): 1894-1905. doi: 10.1056/NEJMoa1915745
[16] Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma[J]. J Hepatol, 2022, 76(4): 862-873. doi: 10.1016/j.jhep.2021.11.030
[17] Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase Ⅲ Trial[J]. J Clin Oncol, 2020, 38(3): 193-202. doi: 10.1200/JCO.19.01307
[18] Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial[J]. Lancet Oncol, 2022, 23(1): 77-90. doi: 10.1016/S1470-2045(21)00604-5
[19] Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups[J]. Gut, 2021, 70(1): 204-214. doi: 10.1136/gutjnl-2020-321702
[20] Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC[J]. Nature, 2021, 592(7854): 450-456. doi: 10.1038/s41586-021-03362-0
[21] Haber PK, Puigvehí M, Castet F, et al. Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020)[J]. Gastroenterology, 2021, 161(3): 879-898. doi: 10.1053/j.gastro.2021.06.008
[22] MacParland SA, Liu JC, Ma XZ, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations[J]. Nat Commun, 2018, 9(1): 4383. doi: 10.1038/s41467-018-06318-7
[23] Xiao H, Guo Y, Li B, et al. M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects[J]. ACS Cent Sci, 2020, 6(7): 1208-1222. doi: 10.1021/acscentsci.9b01235
[24] DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy[J]. Nat Rev Immunol, 2019, 19(6): 369-382. doi: 10.1038/s41577-019-0127-6
[25] Wang Y, Tiruthani K, Li S, et al. mRNA Delivery of a Bispecific Single-Domain Antibody to Polarize Tumor-Associated Macrophages and Synergize Immunotherapy against Liver Malignancies[J]. Adv Mater, 2021, 33(23): e2007603. doi: 10.1002/adma.202007603
[26] Li SY, An P, Cai HY, et al. Proteomic analysis of differentially expressed proteins involving in liver metastasis of human colorectal carcinoma[J]. Hepatobiliary Pancreat Dis Int, 2010, 9(2): 149-153.
[27] Jiang J, Zhang J, Fu K, et al. Function and mechanism exploration of zinc finger protein 64 in lung adenocarcinoma cell growth and metastasis[J]. J Recept Signal Transduct Res, 2021, 41(5): 457-465. doi: 10.1080/10799893.2020.1825490
[28] Wei CY, Zhu MX, Zhang PF, et al. PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma[J]. J Hepatol, 2022, 77(1): 163-176. doi: 10.1016/j.jhep.2022.02.019
[29] Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia[J]. Nat Genet, 2003, 34(2): 154-156. doi: 10.1038/ng1161
[30] Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9[J]. Nat Genet, 2005, 37(2): 161-165. doi: 10.1038/ng1509
[31] Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease[J]. N Engl J Med, 2006, 354(12): 1264-1272. doi: 10.1056/NEJMoa054013
[32] Liu X, Bao X, Hu M, et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer[J]. Nature, 2020, 588(7839): 693-698. doi: 10.1038/s41586-020-2911-7
[33] Yuan J, Cai T, Zheng X, et al. Potentiating CD8(+) T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling[J]. Protein Cell, 2021, 12(4): 240-260. doi: 10.1007/s13238-021-00821-2
[34] Hobbs HH, Russell DW, Brown MS, et al. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein[J]. Annu Rev Genet, 1990, 24: 133-170. doi: 10.1146/annurev.ge.24.120190.001025
[35] Stein EA, Honarpour N, Wasserman SM, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia[J]. Circulation, 2013, 128(19): 2113-2120. doi: 10.1161/CIRCULATIONAHA.113.004678
[36] Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial[J]. Lancet, 2015, 385(9965): 341-350. doi: 10.1016/S0140-6736(14)61374-X
[37] Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study[J]. Lancet Diabetes Endocrinol, 2017, 5(4): 280-290. doi: 10.1016/S2213-8587(17)30044-X
[38] Rimini M, Kudo M, Tada T, et al. Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib[J]. ESMO Open, 2021, 6(6): 100330. doi: 10.1016/j.esmoop.2021.100330
[39] Suyama K, Iwase H. Lenvatinib: A Promising Molecular Targeted Agent for Multiple Cancers[J]. Cancer Control, 2018, 25(1): 1073274818789361.
[40] Yi C, Chen L, Lin Z, et al. Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC[J]. Hepatology, 2021, 74(5): 2544-2560. doi: 10.1002/hep.31921
[41] Kim SM, Kim SY, Park CS, et al. Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer[J]. Cancers (Basel), 2020, 12(2): 448. doi: 10.3390/cancers12020448
[42] Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway[J]. PLoS One, 2019, 14(2): e0212513. doi: 10.1371/journal.pone.0212513
[43] Liao P, Wang W, Wang W, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4[J]. Cancer Cell, 2022, 40(4): 365-378. e6. doi: 10.1016/j.ccell.2022.02.003
[44] Wang W, Green M, Choi JE, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569(7755): 270-274. doi: 10.1038/s41586-019-1170-y
[45] Gonzalez FJ, Xie C, Jiang C. The role of hypoxia-inducible factors in metabolic diseases[J]. Nat Rev Endocrinol, 2018, 15(1): 21-32.
[46] Foglia B, Sutti S, Cannito S, et al. Hepatocyte-Specific Deletion of HIF2α Prevents NASH-Related Liver Carcinogenesis by Decreasing Cancer Cell Proliferation[J]. Cell Mol Gastroenterol Hepatol, 2022, 13(2): 459-482. doi: 10.1016/j.jcmgh.2021.10.002
[47] Ban HS, Uto Y, Nakamura H. Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016-2020)[J]. Expert Opin Ther Pat, 2021, 31(5): 387-397. doi: 10.1080/13543776.2021.1874345
[48] Schumacher TN, Thommen DS. Tertiary lymphoid structures in cancer[J]. Science, 2022, 375(6576): eabf9419. doi: 10.1126/science.abf9419
[49] Sautès-Fridman C, Lawand M, Giraldo NA, et al. Tertiary Lymphoid Structures in Cancers: Prognostic Value, Regulation, and Manipulation for Therapeutic Intervention[J]. Front Immunol, 2016, 7: 407.
[50] Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response[J]. Nature, 2020, 577(7791): 549-555. doi: 10.1038/s41586-019-1922-8
[51] Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma[J]. Nature, 2020, 577(7791): 561-565. doi: 10.1038/s41586-019-1914-8
[52] Petitprez F, de Reyniès A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma[J]. Nature, 2020, 577(7791): 556-560. doi: 10.1038/s41586-019-1906-8
[53] Johansson-Percival A, He B, Li ZJ, et al. De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors[J]. Nat Immunol, 2017, 18(11): 1207-1217. doi: 10.1038/ni.3836
[54] Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation[J]. Sci Transl Med, 2017, 9(385): eaak9679. doi: 10.1126/scitranslmed.aak9679
[55] van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial[J]. Nat Med, 2020, 26(12): 1839-1844. doi: 10.1038/s41591-020-1085-z
[56] Maldonado L, Teague JE, Morrow MP, et al. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions[J]. Sci Transl Med, 2014, 6(221): 221ra13.
[57] Matsubara S, Seki M, Suzuki S, et al. Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors[J]. J Immunother Cancer, 2019, 7(1): 256. doi: 10.1186/s40425-019-0736-4
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