Research Advances of PD-1/PD-L1 Inhibitors Combined with Angiogenesis Inhibitors in Treatment of Advanced Triple-negative Breast Cancer
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摘要:
晚期三阴性乳腺癌较其他亚型乳腺癌的治疗手段少、生存期短、预后差。近年飞速发展的免疫治疗有望延长晚期三阴性乳腺癌的生存时间,但是多项临床研究提示PD-1/PD-L1抑制剂单药治疗晚期三阴性乳腺癌有效率低。新近研究显示抗血管生成药物的治疗不仅可以使血管正常化,抑制肿瘤生长,还可以增强免疫治疗的疗效,与PD-1/PD-L1抑制剂联合治疗有协同增效的作用。本文通过分析PD-1/PD-L1抑制剂和抗血管生成药物的作用机制,回顾关于两药联用治疗晚期三阴性乳腺癌的临床前及临床研究,汇总其疗效及安全性,旨在为晚期三阴性乳腺癌的治疗策略提供新的角度和思路。
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关键词:
- 晚期三阴性乳腺癌 /
- PD-1/PD-L1抑制剂 /
- 抗血管生成药物
Abstract:Advanced triple-negative breast cancer(TNBC) has less treatments, shorter survival time and poorer prognosis than other subtypes of breast cancer. The rapid development of immunotherapy in recent years is expected to prolong the survival time of advanced TNBC patients, but multiple clinical studies have suggested that PD-1/PD-L1 inhibitor monotherapy have a low efficiency in the treatment of advanced TNBC. Recent studies have shown that the treatment with angiogenesis inhibitors can not only normalize blood vessels and inhibit tumor growth, but also enhance the efficacy of immunotherapy. Angiogenesis inhibitors combined with PD-1/PD-L1 inhibitors have synergistic effects. This article analyzes the mechanism of PD-1/PD-L1 inhibitors and angiogenesis inhibitors, reviews the preclinical and clinical studies on the combination of two types of drugs in the treatment of advanced TNBC and summarizes their efficacy and safety, to provide new perspectives and ideas for the treatment strategy of advanced TNBC.
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0 引言
近年来,恶性肿瘤发病率逐年升高,对人类健康造成严重影响,目前肿瘤的非手术治疗手段主要有放疗、化疗和分子靶向治疗。在机体抗肿瘤效应中,T淋巴细胞介导的细胞免疫起到了关键作用[1]。肿瘤在其发生发展过程中由于基因突变等原因,肿瘤细胞可分泌不同于正常细胞的抗原,诱发人体抗肿瘤免疫应答。免疫应答启动后,免疫细胞识别肿瘤细胞后将肿瘤抗原呈递给T淋巴细胞,激活T淋巴细胞并特异性杀伤肿瘤细胞[2-4]。在免疫应答过程中,需要协同刺激信号的参与才能激活T淋巴细胞,而这些信号需要经过“免疫检查点”进行调控。T淋巴细胞免疫球蛋白黏蛋白(T cell immunoglobulin mucin, TIM)基因家族是一类位于鼠11号染色体上,能够编码一类具有共同氨基酸序列的跨膜糖蛋白的基因。人类TIM基因家族包括TIM-1、TIM-3和TIM-4,其中TIM-3是TIM基因家族中的重要成员,其作为一种负性调节分子选择性地在活化的Thl细胞表面表达,目前研究发现TIM-3也在CD8+T淋巴细胞、Thl7细胞、Treg细胞、NK细胞及肿瘤浸润性淋巴细胞上表达,同时,研究发现在肝癌、白血病、多发性骨髓瘤、肺癌、胃癌、黑色素瘤、宫颈癌等肿瘤细胞上亦可表达[5-8]。本文将分TIM-3结构、TIM-3配体、TIM-3在肿瘤的表达及其免疫调节机制和TIM-3的免疫治疗等部分分别对TIM-3在肿瘤免疫研究领域的最新进展进行综述。
1 TIM-3结构
2001年,McIntire在寻找小鼠哮喘易感致病基因时发现了一组新的基因家族,经过基因组分析及定位克隆技术鉴定,将其命名为TIM基因家族,该家族基因拥有免疫球蛋白Ⅴ区和黏蛋白区组成的结构,TIM基因能够编码包括信号肽区、免疫球蛋白区、黏蛋白区、跨膜区和胞内尾区的Ⅰ型跨膜糖蛋白。小鼠TIM基因定位于染色体的11Bl.1T细胞和气道表型Tapr(T-cell and airway phenotype regulator)基因座位区域,目前发现了8个基因家族成员(TIM-1~TIM-8)[5-6]。人类TIM基因家族与小鼠基因家族相比具有高度同源性,其定位于染色体5q33.2上,多项研究表明这一染色体区域与免疫性疾病和肿瘤性疾病高度相关[7-8]。
人类TIM基因家族包括TIM-1、TIM-3和TIM-4,其中TIM-3是TIM基因家族中的重要成员,其作为一种负性调节分子选择性地在活化的Thl细胞表面表达,目前研究发现TIM-3也在CD8+T淋巴细胞、Thl7细胞、Treg细胞、NK细胞及肿瘤浸润性淋巴细胞上表达,同时也在多种肿瘤细胞上表达。小鼠TIM-3基因编码的Ⅰ型膜蛋白包含有281个氨基酸,免疫球蛋白Ⅴ区和丝氨酸、苏氨酸残基构成的黏蛋白区共同组成其胞外区。6个酪氨酸构成了胞质区,而其中1个属于酪氨酸残基被磷酸化。人TIM-3与小鼠有63%氨基酸同源序列,其中在胞质区77%氨基酸序列具有高度同一性,包含有1个保守的酪氨酸磷酸化残基。小鼠TIM-3分为全长跨膜型TIM-3(full-length membrane-anchored form of Tim-3, flTIM-3)和可溶型TIM-3(soluble form of Tim-3, sTIM-3)。flTIM-3长度约903 bp,包含有信号肽、免疫球蛋白Ⅴ区、黏蛋白区、跨膜区及胞浆区。sTIM-3长度约800 bp,仅含有信号肽、免疫球蛋白Ⅴ区及胞质区[8]。TIM-3免疫球蛋白IgV区的FG环和CC环形成一个裂缝结构,这个结构与非Galectin-9配体结合高度相关。既往研究表明IL能激活T淋巴细胞激酶,从而磷酸化TIM-3胞内尾区的1个酪氨酸基团,TIM-3与配体相结合能提高酪氨酸磷酸化程度,表明该基团在调节T淋巴细胞免疫应答的信号转导中起到重要作用[9-10]。
2 TIM-3配体
2.1 Galectin-9
半乳糖凝集素-9(Galectin-9)是S型凝集素家族中的一员,是一类由130个氨基酸残基构成的具有β-半乳糖结合活性的一类分子。Galectin-9主要在人和鼠的脾脏及淋巴组织中表达,在T淋巴细胞、嗜酸性粒细胞、内皮细胞、DC细胞和NK细胞均可高表达,并由多种细胞共同参与合成和表达[11-12]。Galectin-9在CD8+小鼠淋巴瘤细胞高表达,被鉴定为TIM-3的配体。当Galectin-9与T淋巴细胞表面的TIM-3相结合,为TIM-3释放负性共刺激信号,诱导T淋巴细胞发生耗竭,规避免疫系统监视,发生免疫逃逸。当Galectin-9加入终末分化的Thl和Th2细胞后,细胞出现Ca2+内流和Thl细胞凋亡,而在Th2细胞和TIM-3的Thl细胞则不会发生此现象,表明Galectin-9依赖结合TIM-3诱导Thl细胞死亡,并发挥下调细胞免疫应答的功能[13-15]。
2.2 HMGB1
高迁移率家族蛋白1(high mobility group box 1,HMGBl)是一类由215个氨基酸残基组成的具有高度保守性的染色质蛋白,由A-box、B-box和1个酸性的羧基末端三个结构域构成。它属于参与DNA转录调节过程的DNA结合蛋白,在核小体的稳定和促进核转录过程中起到重要作用[16]。TIM-3在肿瘤浸润树突状细胞(dendritic cell, DC)高表达,并可与配体HMGB1结合,通过阻断Toll样受体及细胞质中DNA和RNA相关的免疫反应,来抑制核酸介导的固有免疫反应,导致肿瘤免疫逃逸,减弱DNA预防治疗及化疗的效果。细胞在应激状态下,可分泌并释放HMGB1到胞外,通过与细胞表面Toll样受体等结合,参与炎性反应、细胞增殖和迁移等多种复杂的生物学行为[17]。TIM-3竞争性结合HMGBl的A-box结构域后,干扰核酸进入细胞内的路径、抑制HMGBl功能、破坏Toll样受体和胞内传感器参与的固有免疫应答[18]。在黑色素瘤细胞表达的HMGB1与内皮细胞表面TIM-3结合,激活肿瘤细胞NF-κB信号通路,促进肿瘤细胞增殖、增强肿瘤细胞抗凋亡能力,并促进肿瘤细胞发生转移[19]。因而,TIM-3在HMGB1介导的抗肿瘤免疫应答中起到抑制作用,进一步促进了肿瘤免疫逃逸的发生。
2.3 磷脂酰丝氨酸
TIM-3最初被描述为激活Th1淋巴细胞,但最近被证明也是磷脂酰丝氨酸(phosphatidylserine, PS)的受体并介导吞噬细胞,PS又称复合神经酸,是一类带负电荷的磷脂,正常情况下仅在细胞膜内侧分布,是细胞膜内的活性物质,大多存在于大脑细胞中[20]。当细胞发生凋亡,TIM-3在PS-N-末端IgV区域与一个Ca2+结合,实现从膜内侧往外侧转运。吞噬细胞识别凋亡细胞表面PS,吞噬并清除凋亡细胞。鼠类的TIM-3利用免疫球蛋白Ⅴ区FG环来识别凋亡细胞,提示TIM-3可能是PS的一个细胞膜受体,同时,给予小鼠TIM-3单抗后,脾脏内出现大量的凋亡细胞[21]。另一项研究表明,TIM-3+CD8+DC细胞参与凋亡细胞的吞噬过程,并将凋亡细胞表面结合抗原呈递给CD8+T淋巴细胞,提示TIM-3在PS的识别过程中起到重要作用[22]。
3 TIM-3在肿瘤中的表达及其免疫调节机制
机体的免疫功能和肿瘤的发生发展有高度相关性,免疫系统能识别并监视肿瘤细胞,最终将肿瘤细胞从人体清除,然而肿瘤细胞也可能通过免疫逃逸规避机体对肿瘤的免疫应答。在机体抗肿瘤过程中,T淋巴细胞介导的细胞免疫发挥了关键作用,T淋巴细胞功能受到抑制是肿瘤产生免疫逃逸的主要机制之一[23-24]。越来越多的证据表明,TIM-3在多种肿瘤相关的免疫细胞上表达,并对多种细胞因子的分泌起到重要的调节作用,参与肿瘤免疫逃逸和免疫应答。
3.1 TIM-3对T淋巴细胞功能的影响
当机体发生肿瘤病变时可导致T淋巴细胞耗竭。近年来人们比较热衷于开展对TIM-3和PD-1共表达的T淋巴细胞耗竭的系列研究。既往研究表明阻断TIM-3可以恢复IFN-γ、TNF-α分泌和NY-ESO-1特异性CD8+T淋巴细胞的增殖。在黑色素瘤B16F10细胞与酪氨酸相关蛋白-2180-188抗原肽刺激淋巴细胞体外共培养体系中,TIM-3能抑制淋巴细胞增殖和分泌IFN-γ、TNF-α,促进CD8+T淋巴细胞增殖[25]。在鼠肿瘤模型中,在CD8+T淋巴细胞共表达TIM-3和PD-1,当TIM-3与配体结合后,PD1+TIM-3+CD8+T淋巴细胞IFN-γ、TNF-α和IL-2分泌减少,阻断PD-1/PD-1L和TIM-3/Galectin-9信号通路能减轻肿瘤负荷和鼠死亡率[26]。另有一项研究揭示了TIM-3在Treg细胞和CD8+T淋巴细胞高表达时,胃癌患者的预后较差。然而当处于无症状性或者幽门螺杆菌感染时,TIM-3的表达与其并无直接相关性[27]。近期一项关于骨肉瘤的研究结果提示,TIM-3抗原在骨肉瘤患者外周血T淋巴细胞中异常表达,与骨肉瘤疾病进展相关。通过检测82例骨肉瘤患者和60例健康者外周血T淋巴细胞TIM-3表达,结果发现晚期转移和肿瘤病理骨折的肿瘤患者TIM-3 CD4+T淋巴细胞和CD8+T淋巴细胞中表达高于早期无转移和肿瘤病理骨折的患者。此外,TIM-3 CD4+T淋巴细胞和CD8+T淋巴细胞患者总体生存率较差。总之,TIM-3可能是一个潜在的骨肉瘤诊断和预后判定的生物标志物[28]。以上研究提示TIM-3和T淋巴细胞耗竭相关,TIM-3在肿瘤免疫中发挥T淋巴细胞应答的负性调控作用。
3.2 TIM-3对髓系来源抑制细胞的影响
髓系来源抑制细胞(myeloid derived suppressor cells, MDSCs)是一群髓系来源的异质细胞,活化后可抑制机体抗肿瘤免疫反应,促进肿瘤免疫逃逸和发生发展[29]。近期一项研究提出了一个科学假设:TIM-3/galectin-9可能通过促进骨髓衍生抑制细胞生长分化,成为与肿瘤相关的巨噬细胞,为白血病干细胞的存活提供了新的途径[30]。假如这个结论成立,将为白血病免疫治疗开辟新的路径。另一项研究揭示了TIM-3/galectin-9作为一个新的通路,在调节CD11b+Ly-6G+MDSCs的免疫反应中起到重要作用[31]。
3.3 TIM-3对DC的影响
研究发现TIM-3在DC也可表达,有研究表明肿瘤浸润DCs可通过调节TIM-3/HMGB1信号通路抑制核酸介导的先天免疫反应。该研究发现激活TIM-3/HMGB1信号通路可干扰核酸进入细胞内,影响DNA合成和化疗的效果,促进免疫原性核酸释放并导致肿瘤细胞死亡[32]。该研究结果对于定义核酸介导的肿瘤微环境抑制抗肿瘤免疫机制有重要意义。
3.4 TIM-3对NK细胞的影响
TIM-3已被证明在调节NK细胞功能中起到重要作用。一项关于肺腺癌的研究表明调节TIM-3在CD3-CD56+细胞和CD3-CD56-细胞高表达。此外,在肺腺癌患者淋巴结转移或肿瘤T3-T4阶段患者CD3-CD56+NK细胞高表达TIM-3。进一步分析表明,CD3-CD56+细胞NK细胞高表达TIM-3是肺腺癌患者总生存期较短的独立相关因素。重要的是,敲除TIM-3信号和加入抗TIM-3抗体导致外周血NK细胞的细胞毒性和IFN-γ分泌增强。他们的数据表明TIM-3在NK细胞的表达水平可以作为人类肺腺癌预后的生物标志物并支持TIM-3作为免疫治疗新目标和新策略[33]。另一项在胃癌中的研究发现,胃癌患者NK细胞中TIM-3的表达水平明显高于健康对照组的水平。临床分析表明NK细胞中TIM-3水平与肿瘤进展相关。在荷瘤小鼠模型中,发现NK细胞TIM-3水平随着肿瘤生长而增加,表明肿瘤恶化可能诱发TIM-3在NK细胞中表达,T-bet参与调节NK细胞中TIM-3表达,并且TIM-3表达水平与胃癌进展高度相关[34]。
4 TIM-3免疫治疗
TIM-3融合蛋白是通过TIM-3胞外段制备的重组融合蛋白。因其含有TIM-3和胞外段配体结合的结构域,能够与膜TIM-3竞争性结合TIM-3配体,抑制细胞TIM-3信号通路。TIM-3融合蛋白能够通过阻断TIM-3信号通路影响DC细胞极化,诱导Thl产生免疫应答并产生细胞毒性,从根本上抑制肿瘤生长[35]。
TIM-3抗体是利用TIM-3胞外段制备的,分为激动性抗体和中和性抗体。激动性抗体主要通过激活TIM-3信号通路,而中和性抗体主要通过抑制TIM-3信号通路。因为TIM-3主要起到负性调控免疫应答的作用,在肿瘤免疫研究中多采用抑制TIM-3信号通路的中和性抗体[3, 36]。结果发现应用抗TIM-3抗体后,黑色素瘤和肝细胞癌患者能够抑制T淋巴细胞耗竭,增强免疫应答功能,应用抗TIM-3抗体可以促进T淋巴细胞中IL-γ介导的抗肿瘤免疫并抑制肿瘤生长[37]。近期的一项研究表明TIM-3在PD-1耐药的动物T淋巴细胞中高表达。在独立实验中,当抗TIM-3抗体与抗PD-1药物联用时可抑制抗PD-1治疗耐药性的产生。对2例曾接受抗PD-1治疗后疾病进展的肺腺癌患者的样品进行了验证研究,结果表明使用抗PD-1疗法治疗失败与限制抗肿瘤免疫反应的免疫检查点上调有关[38]。临床相关研究发现,联合封锁PD-1和TIM-3信号通路可显著提高抗肿瘤效应,大幅抑制肿瘤的生长,有高达50%的荷瘤小鼠在接受联合治疗后达到CR[39]。
5 小结
TIM-3是重要免疫检查点分子,具有多种生物学功能。TIM-3在不同的免疫细胞中的表达不同,同时扮演的功能也各不相同,TIM-3主要在CD4+Th1和CD8+细胞毒性T淋巴细胞中高表达,参与免疫应答的协同抑制作用。在由其配体galectin-9激活后,TIM-3会抑制效应T淋巴细胞的活性,并引起外周耐受,进而发生免疫逃逸,在肿瘤T淋巴细胞损耗中起着关键作用。因此,进一步研究TIM-3及其配体结构特征、在肿瘤中的表达及其调控免疫反应的机制对TIM-3免疫治疗将起到关键作用,将为肿瘤治疗开拓一片新的天地。
Competing interests: The authors declare that they have no competing interests.作者贡献黄世芬:文献的搜集整理及稿件的撰写令晓玲:选题和文章架构的确定及文稿的修改 -
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