修回日期: 2022-08-01
接受日期: 2022-09-20
在线出版日期: 2022-10-08
热消融是肝脏肿瘤的重要治疗手段之一, 但术后复发率高. 据报道, 热消融可触发肿瘤相关抗原(tumor-associated antigens, TAAs)释放, 从而启动抗肿瘤免疫应答. 然而, 由于抗原呈递障碍、肿瘤抑制性免疫微环境形成、瘤床乏氧乏血供等原因, 该抗肿瘤免疫效应无法有效抑制肿瘤复发. 因此, 联合免疫治疗以增强其抗肿瘤免疫效应, 可改善肿瘤热消融的长期疗效. 然而, 游离免疫药物存在靶向性差且半衰期短的缺点. 纳米材料具有可修饰性强、药物配比可控、靶向性好等优势. 学者们针对热消融后的肿瘤免疫微环境特征, 设计了可刺激抗原呈递、重塑肿瘤免疫微环境、提高肿瘤基质渗透性的纳米免疫药物, 在增效肿瘤热消融联合免疫治疗应用中颇见成效. 本文重点论述纳米材料在肿瘤消融联合免疫治疗的作用.
核心提要: 本文重点从增强肿瘤热消融术后抗原提呈、逆转抑制性免疫微环境两个方面, 论述纳米材料在增效肝脏肿瘤热消融术联合免疫治疗中的作用, 及其临床转化所面临的挑战.
引文著录: 郭焕玲, 谢晓燕, 徐明. 浅谈纳米材料在肝脏肿瘤热消融联合免疫治疗中的应用. 世界华人消化杂志 2022; 30(19): 829-837
Revised: August 1, 2022
Accepted: September 20, 2022
Published online: October 8, 2022
Thermal ablation is one of the important treatments for liver tumors, but the postoperative recurrence rate is high. Thermal ablation has been reported to trigger the release of tumor-associated antigens, which in turn initiates antitumor immune response. However, this anti-tumor immune effect cannot effectively suppress tumor recurrence due to the obstacles of antigen presentation, the formation of tumor-suppressive immune microenvironment, and the hypoxic and hypovascular tumor microenvironment. Therefore, using immunotherapy to enhance the antitumor immune effect after thermal ablation is a potential strategy to improve the prognosis of tumor patients. However, free immune drugs have the disadvantages of poor targeting and short half-life. Nanomaterials have the advantages of strong modifiability, controllable drug ratio, and excellent targeting. Based on the characteristics of the tumor immune microenvironment after thermal ablation, scholars have designed nano-immunopharmaceuticals that can increase the tumor permeability of immune drugs, stimulate antigen presentation, and reshape the tumor immune microenvironment. This review focuses on the role of nanomaterials in tumor ablation combined with immunotherapy for liver tumors.
- Citation: Guo HL, Xie XY, Xu M. Application of nanomaterials in combined thermal ablation and immunotherapy for liver tumors. Shijie Huaren Xiaohua Zazhi 2022; 30(19): 829-837
- URL: https://www.wjgnet.com/1009-3079/full/v30/i19/829.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i19.829
据2020年GlOBOCAN estimates统计, 在全球范围内, 估计有1930万新癌症病例和近1000万癌症死亡病例[1], 可见癌症防控形式依然严峻. 肿瘤热消融术, 是通过高温诱导治疗区域内肿瘤细胞发生不可逆的损伤, 从而实现原位灭活肿瘤的一种局部治疗手段[2]. 相较于手术、放疗、化疗等传统的癌症治疗手段, 热消融术具有微创、疗效确切、对肝肾功能损伤小、住院周期短、可治疗肿瘤类型广泛等优势, 因而已成为肝脏肿瘤的重要治疗手段之一[3]. 然而, 对于复杂病例[包括影像引导显示不清、病灶贴近大血管、肿瘤呈侵袭性不规则生长、病灶贴近重要脏器、微血管侵犯(microvascular invasion, MVI)阳性的小肝癌等], 热消融往往难以完全消融肿瘤, 易存在术后肿瘤细胞残瘤, 导致术后复发率大大增加[4-7]. 此时, 需通过联合系统治疗以积极抗癌.
热消融治疗可触发肿瘤相关抗原(tumor-associated antigens, TAAs)的释放, 从而诱导机体启动抗肿瘤免疫应答, 然而, 该免疫效应难以有效抑制肿瘤复发. 其潜在原因包括: (1)TAAs的抗原呈递不足. 一方面, 热消融后所释放的TAAs抗原性不足. 由于过高温对TAAs免疫原性的破坏[8]、肿瘤灌注低、高间质压[9]不利于TAAs向机体释放, 可导致TAAs的抗原提呈不足. 另一方面, 残余肿瘤可通过诱导抗原提呈细胞(antigen presenting cells, APC)抗原提呈功能失调[10], 逃避抗肿瘤免疫攻击; (2)残余肿瘤诱导抑制性肿瘤免疫微环境形成. 研究表明, 热消融术后后期, 残余肿瘤细胞程序性死亡配体-1(programmed cell death ligand-1, PD-L1)表达上调、细胞毒性T淋巴细胞(cytotoxic T lymphocytes, CTL)数量减少而CTL表面PD-1表达上调、肿瘤局部和外周血中骨髓来源抑制细胞(myeloid-derived suppressor cells, MDSC)显著增加、转化生长因子-β(transforming growth factor-β, TGF-β)水平升高, 从而抵抗热消融诱导的抗肿瘤免疫效应[11-14]; (3)热消融后实体肿瘤的高间质压、乏氧、乏血供微环境, 导致抗肿瘤免疫细胞浸润受限[15,16]. 因此, 通过热消融联合免疫治疗逆转肿瘤免疫微环境, 对抑制热消融后肿瘤复发具有重要临床价值. 然而, 由于免疫治疗靶点的非特异性, 游离免疫药物易致免疫相关毒副作用, 这大大限制了药物的临床应用.
纳米材料具有可修饰性强、生物相容性好、药物配比可控等优势, 通过设计具备肿瘤微环境及外响应性的智能响应型纳米药物[17,18], 可优化热消融温度、捕获TAAs并辅助APC递送、共递送免疫佐剂等以刺激抗原呈递功能、靶向免疫抑制靶点以逆转免疫抑制微环境、增加血管渗透性并改善乏氧以增强效应免疫细胞的募集, 从而增效肿瘤消融联合免疫治疗疗效. 因此, 本文拟重点阐述纳米材料如何在增效肿瘤热消融联合免疫治疗中发挥作用, 并进一步讨论其临床应用前景及面临的挑战, 旨在为热消融联合免疫治疗实体瘤的纳米医学研究提供思路.
射频消融(radiofrequency ablation, RFA)是临床上常用的微创热消融术之一, 其制热原理是, 通过交流电驱动离子高速震动, 离子高速震动受到高阻组织阻碍, 从而产生热量. 其优势是可通过消融针穿刺介导深部肿瘤的治疗, 但热沉效应明显, 且临床能量利用率低, 消融范围较小[19].
微波消融(microwave ablation, MWA)是另一种临床常用的微创热消融术, 是通过发射高频微波(900 MHz以上)使偶极分子的高速旋转而产生大量的热能, 从而导致肿瘤细胞内蛋白凝固. 同时, 微波也可导致靶区离子相互摩擦运动产热, 因此, 消融病灶离子的数量被认为是影响MWA热能的决定性因素[20]. 与RFA相比, MWA的优势是无热沉效应, 消融面积大, 但易造成正常组织的损伤, 不适用于位于重要脏器、大血管旁的肿瘤[19]. 研究报道, 与RFA及冷冻消融相比, MWA诱导的促炎因子白介素1β(interleukin 1β, IL-1β)、白介素6(interleukin 6, IL-6)、热休克蛋白70(heat shock protein 70, HPS70)均显著降低, 这可能与MWA温度较高所致[21].
高能量聚焦超声(high intensity focus ultrasound, HIFU)是一种无创热消融方法, 使用高能聚焦设备将超声能量聚焦于治疗靶点, 从而产生高温(60 ℃以上), 同时产生热、空化和机械效应, 导致蛋白质变性以及肿瘤组织的不可逆凝固和坏死[22]. 然而, 声波在组织中传播时, 特别是在深层组织中, 容易发生能量衰减, 这不可避免地会导致热损失和消融病变处的热沉积不足, 从而降低HIFU的治疗效果[19].
光热与磁热消融是目前纳米研究领域中研究最为广泛的两大热消融手段. 光热消融术(photothermal ablation, PTA)是利用具有光热转换性能的光热剂吸收特定波长的光能转化为高热来灭活肿瘤的一种新兴的消融手段. PTA具有高靶向性、无创、高时空可控性的优势, 但其热利用率低、制热温度有限, 单独治疗往往难以完全根除肿瘤, 限制其临床应用[23]. PTA协同肿瘤免疫疗法已被开发用于实体转移性肿瘤, 包括PTA结合免疫佐剂、CAR-T治疗和免疫检查点抑制剂等等[24,25].
磁热治疗(magnetic hyperthermal therapy, MHT)由于其较好的组织穿透能力, 被临床应用于深部和难以接近的癌症治疗中. 在MHT中, 磁性纳米颗粒在交变磁场作用下通过弛豫损失和磁滞损失产生热[9,26]. 在过去的几十年里, MHT在脑癌、前列腺癌和食管癌的治疗中取得了很好的临床效果[27]. 与其他热消融术相似, MHT也具有热诱导免疫作用. 值得注意的是, 越来越多的研究证明, 部分磁性纳米药物本身即具有免疫刺激作用, 如美国食品药品监督管理局(Food and Drug Administration, FDA)批准的磁性氧化铁纳米颗粒可诱导M1巨噬细胞极化[28], 从而增加肿瘤对免疫治疗的易感性. 而Mn2+可激活STING通路, 提高机体的肿瘤抗原提呈功能[29]. 此外, 磁热剂具备核磁共振成像(magnetic resonance imaging, MRI)成像功能, 可实现免疫治疗引导[28].
理论上, 热消融可在肿瘤原位产生大量的细胞碎片, 从而激活肿瘤特异性抗原激活免疫系统[30,31]. 此外, 在热消融过程中, 一些"危险信号", 如热休克蛋白、损伤相关分子模式(damage-associated molecular patterns, DAMPs)和促炎细胞因子可能被释放, 能够作为免疫刺激剂, 产生有利于抗肿瘤免疫反应的环境[32]. 然而, 在临床实践中, 我们发现该免疫效应并不足以抑制肿瘤的生长的复发转移. 其潜在原因包括: (1)抗原提呈细胞的抗原呈递不足; (2)过高温破坏肿瘤碎片的抗原性; (3)肿瘤局部高间质压的微环境不利于抗原的递送以及抗肿瘤免疫细胞的渗透. 针对上述问题, 学者们通过灵活设计纳米体系提高热消融后的免疫效应颇有成效.
2.1.1 轻度热消融: 越来越多的研究提出, 高温消融所诱导的免疫效应较轻度热消融弱. Toraya-Brown等[8]报道, 在小鼠皮下结直肠癌模型中, 43 ℃消融治疗可显著抑制对侧肿瘤的生长, 且增加促炎因子的释放, 从而激活TDLN中的树突状细胞(dendritic cells, DC), 进而诱导CD8+T细胞的激活和募集. 相比之下, 45 ℃消融组瘤内激活表型CD8+T细胞无显著变化, 且对侧肿瘤生长未受明显抑制. 蒋文超等[33]采用不同温度热消融治疗小鼠皮下肝癌, 发现与60 ℃、70 ℃、100 ℃相比, 50 ℃消融灶中的CD4+T细胞、CD8+T细胞数量及HPS70表达量最高, 提示轻度消融比高温消融更有利于诱导主动免疫效应. 这可能是因为不同的温度可能对细胞因子/趋化因子环境、肿瘤血管系统以及对肿瘤和间质细胞的应激产生了不同水平的影响, 例如, 轻度消融可能增加了血管系统的通透性, 更好地促进了树突状细胞在肿瘤和肿瘤引流淋巴结(tumor draining lymph node, TDLN)之间的运输, 而高热可损伤血管, 造成血栓形成[34]. 可见, 轻度热消融可减少肿瘤抗原等生物分子潜在的热诱导变性[35], 还可改善肿瘤微环境, 包括肿瘤细胞外基质的部分破坏、减少肿瘤间质液、增加血流灌注, 这有利于免疫治疗药物和淋巴细胞的招募和浸润.
(1)轻度光热消融联合免疫治疗: Li等[36]受发热可促发全身免疫效应的启发, 以纳米金(Au)为光热转换剂, 设计了共载免疫佐剂CpG及Au的纳米药物PCN用于轻度PTA. 高通量基因图谱分析鉴定出9个促炎相关基因上调. 凋亡实验表明PCN介导的43 ℃ PTA即可诱导4T1细胞凋亡. 荷4T1乳腺癌肿瘤小鼠实验表明, PCN介导的43 ℃ PTA可显著增加肿瘤血管灌注、促进APC向TDLN迁移、显著增加CD8+T细胞及巨噬细胞募集至瘤床, 强调了轻度热疗在调节免疫微环境优化免疫治疗中的重要作用. Zhang等[37]利用NIR吸收光的聚合物和免疫调节剂制备了具有天然线粒体靶向的双靶向聚合物纳米颗粒(R848@cRGD-PDCS). R848@cRGD-PDCS对肿瘤细胞线粒体的轻度PTA作用可触发精确的原位线粒体损伤, 促进肿瘤相关抗原的释放, 显著增效PD-L1抗体的疗效, 有效抑制了PTA后原发肿瘤、远处肿瘤和肿瘤转移; (2)轻度磁热消融联合免疫治疗: Liu等[38]报道了一种有效且生物安全性好的纳米材料介导的轻度MHT联合免疫治疗策略, 可以根除乳腺癌原发肿瘤, 抑制肺转移, 并控制远处肿瘤的转移和生长. 铁磁涡旋域氧化铁纳米环FVIO介导的轻度MHT上调了4T1乳腺癌细胞上钙网蛋白(calprotectin, CRT)的表达. CRT的表达了传递"吃我"信号, 促进机体免疫系统对癌细胞的识别, 诱导了有效的免疫原性细胞死亡(immunogenic cell death, ICD), 并提高了肿瘤对PD-L1阻断治疗的应答率; (3)轻度超声消融联合免疫治疗: HIFU过程中快速的温度升高可能导致抗原凝固和失活, 从而抑制免疫诱导效应. 与热传统HIFU相比, 使用瞬时高强度重复的声脉冲, 称为机械HIFU(mechanical HIFU), 可更好地控制治疗温度, 更有效地保留抗原, 从而促DC成熟及T细胞浸润以增强免疫应答[32,39,40]. 因此, Li等[41]提出了采用将纳米液滴PPCP NDs与mHIFU照射相结合进行肿瘤治疗的策略, 其中, 纳米液滴可有效提高mHIFU的热转换效率. 荷瘤小鼠体内实验表明, PPCP NDs可通过mHIFU辐照促进ICD, 导致DC成熟比例增加, 肿瘤组织中活化的CD3+、CD4+和CD8+T细胞浸润增强.
尽管轻度消融的免疫效应优于高温消融已被广泛认可, 但不同研究间轻度消融温度不一致, 同一温度下测得的免疫效应也存在相左, 如有研究表明[26], 在大鼠Walker-256癌肉瘤模型中, 相比于42 ℃-46 ℃, 磁介导热疗在50 ℃-55 ℃时诱导了更强的免疫效应. 目前研究的显著差异可能由不同的细胞系和动物模型、热消融部位、热休克蛋白的产生和分泌的途径、细胞外结构所致. 因此, 需要更全面的研究不同温度消融对机体免疫刺激的作用, 并开展临床试验, 获得更为接近临床的实验证据.
2.1.2 抗原的捕获与靶向APC递送: 纳米材料可作为载体平台, 用于热消融后肿瘤相关抗原的捕获、封装、表面修饰或辅助递送至APC中, 这些方法均已证明可有效刺激APC的抗原提呈作用, 从而刺激T细胞的增殖分化、激活和募集.
碳点表面有多个功能基团, 包括羟基, 氨基, 羧基等, 可用于结合RNA或者蛋白[42], 有研究表明糖修饰的碳点可以靶向APC[43], 因此, Zhou等[44]巧妙地利用了碳点的结合特性, 设计了一种由甘露醇修饰的碳点用于捕获MWA后消融灶的肿瘤抗原, 显著增强了树突状细胞的抗原提呈作用, 增强了MWA后的肿瘤免疫效应, 显著抑制了远处肝原位肿瘤的生长, 并有效抑制了肝癌的复发.
Wang等[45]则选择具有强抗原吸附能力的马来酰亚胺聚乙二醇修饰的CuS NPs-PEG-Mal. CuS NPs-PEG-Mal不仅可以作为肿瘤热疗的光热介质, 而且可以吸附肿瘤热疗过程中释放的抗原作为抗原捕获剂, 诱导抗肿瘤免疫应答. 结果表明, 基于CuS NPs-PEG-Mal的PTA明显增加了炎性细胞因子的水平. 在协同抗PD-L1的作用下, CuS NPs-PEG-Mal介导的PTA增强了肿瘤浸润CD8+ T细胞的数量, 抑制了4T1肿瘤模型原发部位和远处肿瘤的生长.
2.1.3 直接激活APC: 新近研究发现, 环磷酸鸟苷-腺苷合成酶(cyclic guanosine monophosphate-adenosine monophosphate synthase, cGAS)-干扰素刺激基因(stimulator of interferon genes, STING)信号通路是机体启动先天性和适应性抗肿瘤免疫的关键通路[46]. 肿瘤来源的DNA可激活抗原提呈细胞APC胞质内的cGAS-STING通路, 释放I型干扰素及Th1型细胞因子, 诱导APCs成熟活化, 促进肿瘤相关抗原的交叉呈递, 诱导抗原特异性T淋巴细胞的分化、增殖, 诱导CTLs的肿瘤浸润[47]. 在小鼠皮下肿瘤模型中, 我们发现[48], RFA术后残余肿瘤中STING通路激活不足, 并进一步开发了一种共载STING激活剂与抗PD-L1抗体的纳米药物P-LPD, 结果表明, STING激活剂显著增加了肿瘤引流淋巴细胞中的成熟DCs、肿瘤浸润CD8+T细胞与CD4+T细胞, 增效PD-L1阻断疗效, 有效抑制了RFA术后残余肿瘤的生长和复发. Zhan等[49]将STING激活剂cGAMP与硫化亚铁共载于温敏脂质体中, 硫化亚铁载NIRII的照射下可发生光热效应, 从而触发cGAMP释放, 增效了PTA后APC的激活及ICD效应.
Rho相关激酶ROCKs是RhoA的一种关键下游效应因子, 可抑制APC的吞噬能力, 从而干扰其抗原提呈功能[50]. Y27632可有效阻断ROCKs, 然而其静脉给药靶向能力差[51]. 因此, Chen等[10]采用PLGA-PEG-PLGA(PPP)水凝胶物理包裹Y27632, 在皮下黑色素瘤RFA术后注射至肿瘤部位. 随着Y27632从PPP体系中持续释放, 肿瘤与TDLN中的成熟DC显著增加, 有效激活了T细胞介导的抗肿瘤免疫效应, 提高了RFA的治疗效率.
2.1.4 免疫佐剂: 免疫佐剂是一种非特异性免疫增强剂, 可增强机体对抗原的免疫应答. 热消融诱导的TAAs与免疫佐剂联合可以形成原位疫苗, 增强TAAs的免疫原性, 有效启动机体肿瘤免疫. 常用的免疫佐剂主要是toll样受体(toll-like receptor, TLR)激动剂, 包括胞嘧啶-磷酸-鸟嘌呤寡脱氧核苷酸(cytosine-phosphate-guanine oligodeoxynucleotides, CpG ODNs), 一种TLR-9激动剂), Imiquimod(R837, 一种TLR7激动剂), 单磷酸脂a(monophosphate A, MPLA), 一种TLR-4激动剂等, 这些TLR激动剂能够模仿病原体相关分子模式, 以促进DC成熟并增加免疫相关细胞因子的分泌[52]. 然而, 免疫佐剂的临床应用面临着严峻的挑战, 如生物分布特征不理想、严重的副作用和体内不稳定等, 这些都显著削弱了免疫佐剂的治疗效果[9].
一方面, 纳米载体可被用于改善免疫佐剂递送, 增强其抗肿瘤效应. 另一方面, 纳米载体可介导免疫佐剂与抗原同时递送至APC中, 增强抗原的抗原刺激作用[53]. Han等[54]利用聚(乳酸共乙醇酸)(poly lactic-co-glycolic acid, PLGA)封装R837, 或MPLA, 以获得PLGA-R837或PLGA-MPLA纳米颗粒作为纳米佐剂. 经RFA或HIFU消融肿瘤后, 在局部注射PLGA-R837或PLGA-MPLA, 刺激肿瘤部位和TDLN上的未成熟树突状细胞和幼稚T细胞. 联合抗CTLA-4治疗, 显著抑制了远处肿瘤, 并有效预防了肿瘤复发. 该治疗方案所用制剂均已获FDA批准, 因而该纳米佐剂联合热消融及ICB的治疗策略具有较好的临床应用前景. Cao等[55]则使用临床使用的海藻酸盐水凝胶包载免疫佐剂R837, 制备得可注射的水凝胶免疫制剂, 于MWA术前注射至肿瘤部位, 由于水凝胶中富含离子可增效MWA的热效应, 而热促发释放的R837, 瘤床高剂量的R837可促进APC识别并提呈MWA后释放的TAAs, 从而诱导强大的抗肿瘤免疫效应, 进而抑制原位及远处转移肿瘤.
免疫佐剂的引入为提高热消融肿瘤释放的原位自体肿瘤疫苗的免疫原性和提高免疫应答率提供了一种切实可行的方法. 然而, 仍需推进免疫佐剂纳米药物研发, 优化免疫佐剂生物安全性和有效性, 推进临床转化.
2.2.1 PD-1/PD-L1阻断: 程序性死亡受体-1/程序性死亡配体-1(programmed cell death protein-1/programmed cell death ligand 1, PD-1/PD-L1)拮抗治疗因在晚期癌症患者中显示出了良好的疗效而备受瞩目[56,57]. 多项研究表明, 肿瘤内CTL浸润不足是限制PD-1/PD-L1拮抗治疗的疗效的关键因素[58,59]. CTL, 包括CD4+、CD8+T细胞等, 是PD-1/PD-L1阻断治疗的靶细胞, 直接参与抗肿瘤免疫反应并维持免疫监视[60]. 热消融可诱导残余肿瘤表面PD-L1表达上调[11,12,48], 从而逃逸机体免疫监督. 此外, 通过增效热消融术后的免疫效应, 可有效增加病灶的CD8+T细胞浸润, 即将"冷肿瘤"转化为"热肿瘤", 增效PD-1/PD-L1阻断疗效. 因此, 热消融与PD-1/PD-L1阻断治疗具有协同效应. 然而PD-1/PD-L1抗体的临床应用仍受限于因抗体非靶向输送导致irAEs, 包括肝炎、肺炎等[61-63]. 纳米材料可通过提高抗体的靶向作用、延长抗体在肿瘤局部的滞留时间、介导PD-1/PD-L1相关小分子药物或治疗基因替代抗体治疗等降低irAEs风险, 并提高热消融联合PD-1/PD-L1阻断治疗疗效.
为减少PD-L1抗体的非靶向递送, 我们团队[48]报道了一种共同负载抗PD-L1抗体与STING通路激活剂DMXAA的纳米脂质体, 其表面由可响应性脱落的抗体屏蔽壳层PEG修饰, 该PEG层仅在肿瘤部位酸性条件下响应型脱落, 使得抗体在外周循环可避免与正常机体细胞非靶向结合, 从而提高抗体在肿瘤组织的富集, 减少所负载抗体与STING激活剂的非靶输送, 显著提高了不完全射频消融术后残余瘤对PD-L1抗体治疗的应答率. Han等[64]则利用血小板的炎症趋向特性, 制备了抗PD-L1抗体偶联的工程血小板, 通过小鼠皮下乳腺癌模型, 证明了抗体偶联血小板可以有效靶向PTA后的残余肿瘤. 这种基于血小板的给药策略可扩展到其他类型的局部治疗后的靶向给药, 包括光动力治疗、高强度聚焦超声消融治疗, 甚至放疗.
仿生纳米载体因其可有望实现个性化精准治疗而备受关注. 其中, 从癌细胞中提取的癌细胞膜可以保留抗原多样性以进行免疫逃逸, 以及来自癌细胞的自然特性的同型结合能力[65,66], 从而提高特异性结合的靶向效率, 减少机体的免疫清除. Fang等[67]采用CT26癌细胞膜包载光热剂FePSe3与抗PD-1肽(anti-PD-1 peptide, APP), 制备得纳米药物FePSe3@APP@CCM, 通过近红外激光激发下的光热疗法FePSe3@APP@CCM诱导高效肿瘤消融和抑制肿瘤生长, 进一步激活免疫反应. 此外, APP阻断PD-1/PD-L1通路, 激活CTL, 产生强大的抗癌免疫力.
一种光热基因组编辑策略通过CRISPR/cas9进行PD-L1基因组编辑, 并联合轻度PTA诱导的ICD来改善PD-1/PD-L1阻断治疗[68]. 该策略依赖于超分子阳离子金纳米棒, 不仅作为载体递送靶向PD-L1的CRISPR/Cas9, 还吸收第二近红外窗口NIR-Ⅱ光能, 转化为轻度热疗, 诱导ICD和Cas9的基因表达. PD-L1的基因组破坏通过改善树突状细胞向T细胞的转化, 进而促进CTL向肿瘤浸润, 从而将免疫抑制的肿瘤微环境重新编程为免疫活性的肿瘤微环境, 从而显著增强ICB治疗. 这种治疗方式极大地抑制了原发性和转移性肿瘤的活性, 并对复发性和复发性肿瘤表现出长期的免疫记忆效应.
2.2.2 靶向抑制Tregs: 调节性T细胞(regulatory T lymphocyte, Tregs), 在细胞核中特异表达转录因子FoxP3, 在细胞表面特异表达CD25和细胞毒性T淋巴细胞抗原4(cytotoxic T lymphocyte antigen 4, CTLA-4), 是一种功能独特的T细胞亚群, 参与维持免疫自我耐受和内稳态[69]. 目前正在研究的一个问题是如何靶向耗尽Treg来增强肿瘤免疫力. CTLA-4与CD28共享一对表达在APCs表面的B7分子配体, 在T细胞激活中介导相反的功能. CD28协同T细胞受体信号介导T细胞共刺激, 而配体与CTLA-4的相互作用可抑制T细胞反应[70]. RFA与CTLA-4阻断治疗的联合治疗已在临床试验中初显疗效. Zhou等[71]报道, MWA治疗后联用抗CTLA-4抗体治疗后, 乳腺癌患者外周血中的CD4(+) T细胞共刺激信号增强, ICOS+CD4+T细胞频率增加, 激活表型CD8+T细胞显著增加. Tremelimumab联合RFA或TACE(NCT01853618)被推荐为晚期HCC患者的辅助治疗, 约有26%的患者体现出较好的部分反应[72].
与PD-1/PD-L1阻断治疗相同, CTLA-4阻断治疗同样面临着irAEs的挑战, 而目前纳米药物介导的热消融联合CTLA-4阻断治疗所用制剂均为游离抗体, 尚无优化抗CTLA-4抗体递送的研究, 值得进一步探讨. 此外, 热消融术后对不同肿瘤类型的CTLA-4表达的影响未有报道.
2.2.3 靶向抑制髓系免疫抑制细胞: Xu等[73]研究报道, 不完全微波消融术诱导了持续的免疫抑制微环境, 主要表现为髓系抑制细胞增加, 包括髓源性抑制细胞MDSC和肿瘤相关局势细胞TAM的浸润增多, 最终促进肿瘤进展. 该团队选用选择性PI3Kγ抑制剂IPI549靶向抑制髓系免疫抑制细胞, 通过设计可注射的ROS敏感原位水凝胶作为载体, 分别制备了共载抗PD-1抗体与IPI549的水凝胶aPD-L1&IPI549@Gel[70], 以及共载化疗药物OX与IPI549的水凝胶OX&IPI549@Gel[74], 治疗MWA后的残余肿瘤, 均获得较好的疗效.
2.2.4 血管正常化: 一氧化氮(nitric oxide, NO)是调节人类生命活动的重要信号分子, 可诱导血管内皮生长因子、碱性成纤维细胞生长因子等内源性血管生成因子的表达[75]. 因此, NO可使肿瘤血管正常化, 从而缓解缺氧、逆转抑制性免疫微环境, 如减少Tregs, M2型巨噬细胞, 降低肿瘤免疫检查点的表达. 然而, 与小分子药物类似, NO在体内的低生物利用度限制了其疗效. 为此, Yang等[76]制备了一种热敏型NO供体s-亚硝基硫醇(s-Nitrosothiol, SNO)-共聚物, 用于共递送近红外Ⅱ光热剂IR1061和吲哚胺2,3-双加氧酶1(indoleamine 2, 3-dioxygenase 1, IDO-1)抑制剂1-甲基色氨酸(1-methyl-tryptophan, 1-MT). 通过1-MT干扰IDO-1活性和原位生成NO使肿瘤血管正常化, PTA诱导CD8+ CTLs的募集显著增加, 免疫抑制的免疫微环境被重塑为免疫刺激表型, 有效抑制了原位乳腺癌及转移性乳腺癌.
热消融协同免疫治疗领域已取得系列振奋人心的研究成果, 为肝脏肿瘤患者带来了福音, 但是, 纳米药物在热消融联合免疫治疗中的应用仍处于概念验证阶段, 在进一步的临床转化中面临系列限制. (1)热消融后的免疫效应及免疫逃逸机制仍需进一步系统的临床研究证实, 以更精准地识别治疗靶点. 尽管已有多篇文献报道不同类型热消融治疗后的免疫效应, 但大多数研究仍限于动物研究. 此外, 相关临床研究中, 大多数研究仅限于分析患者外周血的免疫变化, 未能反应消融灶周围免疫微环境. 再者, 大量研究证实, 热消融术后出现"抗瘤"-"促瘤"的免疫微环境变化, 那么, 有必要识别热消融术后的免疫治疗窗口期, 以及探讨有效的序贯治疗方案; (2)提高纳米药物对肿瘤的靶向能力是临床应用的必要和迫切要求. 大多数经静脉给药的纳米药物可以在血液循环过程中被网状内皮系统识别并清除. 因此, 只有一小部分纳米药物可以被输送到肿瘤区域, 这大大降低了预期的治疗效果. 在这方面, 许多创新的方法被用来克服这一问题, 如引入靶向配体, 利用外部磁场进行精确的磁靶向, 以及仿生细胞膜涂层等策略促进免疫逃逸和同源靶向. 然而, 这些改性纳米药物进入生理环境后的稳定性还需要进一步研究[9,77,78]; (3)系统评估应用于热消融协同免疫治疗的纳米药物的生物安全性势在必行. 一些研究表明, 一些纳米颗粒具有潜在风险. 例如, 树突状纳米药物可导致通透性损伤和细胞膜破裂. 纳米医学的药理学和毒理学分析表明, 一旦颗粒尺寸减小到一定程度, 毒性就会急剧增加. 此外, 纳米颗粒很容易吸收大分子, 比如组织或体液中的酶和其他蛋白质, 这就干扰了正常的生物过程. 另外, 纳米药物还会导致吞噬细胞超负荷, 从而引发防御性发热, 降低机体免疫力. 因此, 纳米药物在恶性肿瘤治疗中的应用需要加强对人体毒理学的研究[9]; (4)简化纳米制剂制备工艺. 目前研究报道的纳米载体类型繁多, 尽管设计良好, 但仍需研发基于已获FDA的材料的制备工艺简单且可重复性稳定的纳米免疫制剂.
学科分类: 胃肠病学和肝病学
手稿来源地: 广东省
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科学编辑:张砚梁 制作编辑:张砚梁
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