药学学报

Target	Target based action	Drug name	Active indication	Highest status	Drug ID
IL-10R	IL-10 antagonist	MK-1966	Metastasis	Ph 1 clinical	97334
CSF-1R	CSF-1 antagonist	BLZ-945	Advanced solid tumor	Ph 2 clinical	65977
		SNDX-6352	Advanced solid tumor; cancer	Ph 1 clinical	102739
CSF-1R	CSF-1 antagonist	Emactuzumab	solid tumor	Ph 1 clinical	75408
		IMC-CS4	Cancer; stage Ⅳ melanoma	Ph 2 clinical	65181
		Pexidartinib	Colorectal tumor; glioblastoma	Ph 3 clinical	62957
		AMG-820	Cancer	Ph 2 clinical	65242
		PLX-73086	Giant cell bone tumor	Ph 1 clinical	63157
		Cabiralizumab	Cancer; giant cell bone tumor	Ph 2 clinical	72330
		Sunitinib	Adrenal cortical carcinoma	Launched	12973
		ARRY-382	Advanced solid tumor; NSCLC	Ph 2 clinical	67654
		Masitinib	Melanoma; metastatic breast cancer	Pre-registration	57062
CCR2	CCR2 chemokine antagonist	Plozalizumab	Melanoma	Ph 1 clinical	37472
		PF-4136309	Pancreas tumor	Ph 2 clinical	57818
		BMS-813160	Advanced solid tumor	Ph 2 clinical	58959
		CCX-872	Glioma pancreas tumor	Ph 2 clinical	76959
		Propagermanium	Pancreas tumor	Launched	9896
		Emapticap pegol	Acute myelogenous leukemia	Ph 2 clinical	55127
CXCR4	CXCR4 chemokine modulator	USL-311	Glioblastoma; solid tumor	Ph 2 clinical	69745
		Balixafortide	Cancer; stem cell transplantation	Ph 2 clinical	53573
		Burixafor	Leukemia	Ph 2 clinical	59806
		BL-8040	AML; metastatic pancreas cancer	Ph 2 clinical	61169
		Plerixafor	CLL; glioma; non-Hodgkin lymphoma	Launched	16758
		LY-2510924	Acute myelogenous leukemia	Ph 1 clinical	64322
		GMI-1359	Cancer; inflammatory disease	Ph 1 clinical	75115
		F-50067	Cancer	Ph 1 clinical	69148
		Ulocuplumab	AML; advanced solid tumor	Ph 2 clinical	61526
		PF-06747143	AML	Ph 1 clinical	94079
		X4P-001	Melanoma; renal cell carcinoma	Ph 3 clinical	100250
IDO	IDO inhibitor	Navoximod	Solid tumor	Ph 1 clinical	75832
		Indoximod	AML; brain tumor; hormone refractory	Ph 2 clinical	56777
		Epacadostat	Advanced solid tumor; bladder cancer;	Ph 3 clinical	62577
		NLG-802	Cancer	Ph 1 clinical	105484
IDO	IDO inhibitor	BMS-986205	Cancer; hematological neoplasm	Ph 2 clinical	94239
		PF-06840003	Glioma	Ph 1 clinical	78916
		KHK-2455	Advanced solid tumor	Ph 1 clinical	103225
		IO-101	Metastatic non-small cell lung cancer	Ph 2 clinical	101878

Target	Target based action	Drug name	Active indication	Highest status	Drug ID
IL-10R	IL-10 antagonist	MK-1966	Metastasis	Ph 1 clinical	97334
CSF-1R	CSF-1 antagonist	BLZ-945	Advanced solid tumor	Ph 2 clinical	65977
		SNDX-6352	Advanced solid tumor; cancer	Ph 1 clinical	102739
CSF-1R	CSF-1 antagonist	Emactuzumab	solid tumor	Ph 1 clinical	75408
		IMC-CS4	Cancer; stage Ⅳ melanoma	Ph 2 clinical	65181
		Pexidartinib	Colorectal tumor; glioblastoma	Ph 3 clinical	62957
		AMG-820	Cancer	Ph 2 clinical	65242
		PLX-73086	Giant cell bone tumor	Ph 1 clinical	63157
		Cabiralizumab	Cancer; giant cell bone tumor	Ph 2 clinical	72330
		Sunitinib	Adrenal cortical carcinoma	Launched	12973
		ARRY-382	Advanced solid tumor; NSCLC	Ph 2 clinical	67654
		Masitinib	Melanoma; metastatic breast cancer	Pre-registration	57062
CCR2	CCR2 chemokine antagonist	Plozalizumab	Melanoma	Ph 1 clinical	37472
		PF-4136309	Pancreas tumor	Ph 2 clinical	57818
		BMS-813160	Advanced solid tumor	Ph 2 clinical	58959
		CCX-872	Glioma pancreas tumor	Ph 2 clinical	76959
		Propagermanium	Pancreas tumor	Launched	9896
		Emapticap pegol	Acute myelogenous leukemia	Ph 2 clinical	55127
CXCR4	CXCR4 chemokine modulator	USL-311	Glioblastoma; solid tumor	Ph 2 clinical	69745
		Balixafortide	Cancer; stem cell transplantation	Ph 2 clinical	53573
		Burixafor	Leukemia	Ph 2 clinical	59806
		BL-8040	AML; metastatic pancreas cancer	Ph 2 clinical	61169
		Plerixafor	CLL; glioma; non-Hodgkin lymphoma	Launched	16758
		LY-2510924	Acute myelogenous leukemia	Ph 1 clinical	64322
		GMI-1359	Cancer; inflammatory disease	Ph 1 clinical	75115
		F-50067	Cancer	Ph 1 clinical	69148
		Ulocuplumab	AML; advanced solid tumor	Ph 2 clinical	61526
		PF-06747143	AML	Ph 1 clinical	94079
		X4P-001	Melanoma; renal cell carcinoma	Ph 3 clinical	100250
IDO	IDO inhibitor	Navoximod	Solid tumor	Ph 1 clinical	75832
		Indoximod	AML; brain tumor; hormone refractory	Ph 2 clinical	56777
		Epacadostat	Advanced solid tumor; bladder cancer;	Ph 3 clinical	62577
		NLG-802	Cancer	Ph 1 clinical	105484
IDO	IDO inhibitor	BMS-986205	Cancer; hematological neoplasm	Ph 2 clinical	94239
		PF-06840003	Glioma	Ph 1 clinical	78916
		KHK-2455	Advanced solid tumor	Ph 1 clinical	103225
		IO-101	Metastatic non-small cell lung cancer	Ph 2 clinical	101878

肿瘤微环境及相关靶向药的研究进展

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陈风飞 ¹^,² , 李欣欣 ¹^,² , 孙立 ¹ , 马晓慧 ² , 袁胜涛 ¹^,^*

药学学报 | 综述 2018,53(5): 676-683

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药学学报 | 综述 2018, 53(5): 676-683

肿瘤微环境及相关靶向药的研究进展

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陈风飞¹^,², 李欣欣¹^,², 孙立¹, 马晓慧², 袁胜涛¹^,^*

作者信息

1.中国药科大学, 江苏省新药筛选重点实验室, 江苏南京 210009

2.天士力医药集团股份有限公司创新中药关键技术国家重点实验室, 天津 300410

通讯作者:

* 袁胜涛, Tel:86-25-83271043, E-mail:Yuanst@cpu.edu.cn

Advances in tumor microenvironment and related targeted drugs

Feng-fei CHEN¹^,², Xin-xin LI¹^,², Li SUN¹, Xiao-hui MA², Sheng-tao YUAN¹^,^*

Affiliations

1. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China

2. State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Holding Group Co., Ltd., Tianjin 300410, China

出版时间: 2018-05-12 doi: 10.16438/j.0513-4870.2017-1233

文章导航

摘要

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肿瘤微环境（tumor microenvironment，TME）是肿瘤所处的内环境。作为一个功能单元，其生物学作用贯穿于肿瘤的发生和发展。缺氧、炎症及免疫抑制是TME的三大特征。缺氧信号出现在多条免疫抑制通路中，肠道菌群-慢性炎症-免疫之间同样存在信息交流。可见，TME的三大特征互相关联，形成一个复杂的机制网络，进而影响肿瘤转移。与此同时，TME还阻碍着实体瘤免疫疗法的研发及疗效。因此，寻找有价值的生物标志物以预测疾病的发展；阐明微环境中的机制网络、研发微环境靶向药、开发有效的药物联用策略以避免TME对药效的抵抗，都极具临床价值。

关键词

肿瘤微环境 / 缺氧 / 炎症 / 免疫抑制 / 肠道菌群 / 免疫疗法 / 靶向治疗

Abstract

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Tumor microenvironment (TME) is the internal environment of tumor. As a functional unit, the microenvironment determines the occurrence and development of tumors. Hypoxia, inflammation and immunosuppression are three major characteristics of TME. Hypoxia signals involve in multiple immunosuppressive pathway. There is communication among the gut microbiota, chronic inflammation and immunity. The three characteristics are associated with each other to form a complex network affecting the metastasis of the tumor. TME also influences the development of immunotherapy and efficacy of drugs in solid tumor. Therefore, it is important to identify the valuable biomarkers to predict disease progression, to elucidate the mechanistic networks in the microenvironment, to develop microenvironment targeting drugs and effective drug combination strategies to improve the drug efficacy. All of these have a profound clinical value.

Key words

tumor microenvironment / hypoxia / inflammation / immunosuppressive / gut microbiota / immunotherapy / targeted therapy

引用本文

陈风飞, 李欣欣, 孙立, 马晓慧, 袁胜涛. 肿瘤微环境及相关靶向药的研究进展. 药学学报, 2018 , 53 (5) : 676 -683 . DOI: 10.16438/j.0513-4870.2017-1233

Feng-fei CHEN, Xin-xin LI, Li SUN, Xiao-hui MA, Sheng-tao YUAN. Advances in tumor microenvironment and related targeted drugs[J]. Acta Pharmaceutica Sinica, 2018 , 53 (5) : 676 -683 . DOI: 10.16438/j.0513-4870.2017-1233

正文

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肿瘤微环境(tumor microenvironment, TME)是肿瘤所处的内环境, 主要由肿瘤细胞、基质细胞(包括组织正常上皮细胞、血管内皮细胞、肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、免疫和炎症细胞、脂肪细胞、胶质细胞、平滑肌细胞、骨髓来源未成熟细胞)、细胞外基质以及细胞因子和趋化因子等可溶性物质组成, 是一个复杂的综合系统。该概念在1979年, 由Lord等^[1]首次提出。近40年的研究表明, TME中各种成分之间存在着信息的交流, 形成一个机制网络, 进而影响肿瘤的发展。

1 肿瘤微环境的特征

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肿瘤微环境的特征, 主要有三大类:缺氧、慢性炎症及免疫抑制。三者相辅相成, 形成一个复杂的机制网络, 对肿瘤的发展产生重要作用。

1.1 微环境缺氧

缺氧是所有实体瘤的共性, 通常以肿瘤的中心向外, 缺氧的程度逐渐减弱。研究表明, 瘤内缺氧主要通过缺氧诱导因子(hypoxia-inducible factor, HIF)信号通路来产生后续的生物学反应。在常氧情况下, 脯氨酰羟化酶1~3 (prolyl hydroxylase, PHD1~3)以氧气为底物, 羟化HIF-1/2α的脯氨酸残基, 使得E3泛素酶的希佩尔−林道(VHL, Von Hippel-Lindau)基团能对其进行识别及降解。在缺氧情况下, 上述通路被抑制, 使HIF稳定存在并转位至核内, 与芳烃受体核转位因子(aryl hydrocarbon receptor nuclear translocator, ARNT)形成二聚体。随后, 该二聚体结合到靶基因的缺氧反应元件(hypoxia response element, HRE)上, 同时募集转录共刺激因子如p300/CBP, 以启动靶基因的转录^[2]。HIF参与多条免疫抑制的信号通路。如缺氧诱导HIF-1α高表达, 并与程序性凋亡配体-1 (programmed death-ligand 1, PD-L1)启动子的anHRE结合, 上调骨髓来源免疫抑制细胞(myeloid- derived suppressor cells, MDSC)表面PD-L1的表达^[3]。在转化生长因子-β (transforming growth factor beta, TGF-β)存在下, HIF-1α直接连接到翼状螺旋转录因子P3 (forkhead box transcription factor P3, Foxp3)的启动子区域, 诱导调节性T细胞(regulatory T cell, Treg)的形成^[4]。缺氧诱导瘤内轴突导向因子-3a (semaphorin 3a, Sema-3a)高表达, 募集表达神经纤毛蛋白-1 (neuropilin-1, Nrp-1)的巨噬细胞进入瘤内的缺氧区, 在微环境内白细胞介素(interleukin, IL)- 4/6/10等的作用下极化为M2型。随后, 经HIF-2α, 抑制Nrp-1的表达, 使这些细胞滞留在缺氧区。正因如此, M2常分布在缺氧区而M1则位于常氧区^[5]。此外, HIF-1α上调诱导型一氧化氮合酶(inducible nitric oxide synthases, iNOS)的表达, 促进NO的合成; 而HIF-2α能诱导arginine的表达, 均能直接抑制T细胞活性^[6]。

除了诱发免疫抑制, 缺氧还可激活HIF-1α/ CXCL12/CXCR4通路。趋化因子CXCL12的受体CXCR4表达于单核细胞、内皮细胞和癌细胞等表面, 经CXCL12/CXCR4生物轴, 增强CXCR4⁺细胞对CXCL12的趋向运动, 激活下游多种促癌生物效应^[7]。如CXCR4⁺癌细胞趋向于含氧量相对高的血管而形成血道转移^[8]。CXCR4⁺的M2型巨噬细胞趋向于化疗损伤的血管周围, 促进血管生成, 最终导致化疗后复发、并伴随不可手术的转移^[9] (图 1)。

1.2 微环境慢性炎症

炎症对肿瘤具有双重作用。溶瘤炎症(tumour- disruptive inflammation)可以抑制肿瘤的发展, 而慢性炎症(tumor-promoting chronic inflammation)通过促进癌细胞增殖、基质降解和重塑、血管生成及免疫抑制, 促使肿瘤的发生、侵袭和转移。早在1863年, Virchow就提出“免疫细胞瘤内浸润是慢性炎症的开始”^[10]。在微环境中, 肿瘤相关巨噬细胞(tumor- associated macrophages, TAM)的比例超过50%, 且超过80%的案例表明, 高比例的TAM与不良预后相关^[11]。巨噬细胞是一类多相的细胞。模式识别受体(Toll-like receptors, TLRs)、维甲酸诱导类受体(retinoic acid inducible gene-like receptors, RIGLRs)与脂多糖(lipopolysaccharides, LPS)或损伤相关模式分子(damage associated molecular patterns, DAMPs)等反应, 激活巨噬细胞分化为M1 (IL-12^HIL-10^L)型。干扰素-γ (interferon-γ, IFN-γ)、肿瘤坏死因子(tumor necrosis factor, TNF)-α、粒细胞−巨噬细胞刺激因子(granulocyte-macrophage colony-stimulating factor, GM-CSF)等也可经典激活M1型巨噬细胞, 主要参与抑癌炎症反应, 也能促进辅助性T细胞-1 (T helper-1, Th1)的产生。微环境局部信号分子如IL-4、IL-6、IL-10、前列腺素E2 (prostaglandin E2, PGE2)、巨噬细胞集落刺激因子(macrophage colony-stimulating factor, M-CSF)以及TGF-β, 可替代激活M2 (IL-10^HIL-12^L)型巨噬细胞, 主要参与慢性炎症及Th2细胞的形成, 帮助肿瘤的发生发展^{[12, 13]}。肿瘤微环境中的TAM的极化, 是与肿瘤免疫3E理论(elimination, equilibrium and escape)相平行的动态过程。早期主要为M1型, 与T细胞、干扰素等发挥清除癌细胞的功能, 而到了后期, 则主要为M2型^[13], 对抗免疫杀伤及促进免疫逃逸, 机制之一或为上述的Sema-3a/Nrp-1通路。

随着对肠道菌群的研究, 菌群与慢性炎症的关系逐渐明朗。相比于其他黏膜组织, 胃肠道含有更多的免疫细胞及淋巴结, 对于免疫细胞的发育及功能极其重要, 而肠内菌群便借此影响免疫系统。与菌群−炎症关系最为密切的是结肠癌。IL-10缺陷的小鼠, 由于无法抵抗菌群引起的炎症而结肠癌易感^[14]。肠道黏膜上皮的完整性会因菌群失衡而损坏。随后, 菌群移位、炎性物质脱落(如LPS、polysaccharide A、鞭毛蛋白)或菌群代谢产物的改变, 刺激机体产生IL-6、GM-CSF和TGF-β等, 募集MDSCs和Treg进入TME, 强化促瘤炎症, 并进一步促进肿瘤的生长。当然, 受菌群−炎症影响的肿瘤并不局限于肠内, 也可以是肠外肿瘤如乳腺癌及卵巢癌。研究发现失调的菌群经TLR5刺激机体产生IL-6, 募集MDSCs至TME。随后MDSC分泌腺苷, 诱导γδT细胞表面galectin-1的表达, 从而抑制抗肿瘤免疫, 刺激卵巢肿瘤的进展^[15−17]。诱发菌群失衡的原因包括抗生素、饮食、基因差异、肿瘤源性的炎症或肿瘤患者所接受的抗肿瘤治疗等。维甲酸诱导基因-1 (retinoic acid inducible gene-1, RIG-1)缺陷的小鼠, 表现为菌群失调及结肠癌易感, 原因在于RIG-1能够识别双链RNA病毒, 通过分泌IgA及胰岛再生源蛋白(Reg3γ)来控制菌群的组成^[18]。抗生素(青霉素、万古霉素和硫酸新霉素)引起肠道中拟杆菌骤减而厚壁菌属剧增, 导致脾脏中抗原呈提细胞(antigen presenting cell, APC)难以激活T细胞, 难以向瘤内浸润, 并同时影响Th1类因子的表达, 弱化小鼠免疫而加速移植瘤发展。可见, APC在菌群和抗肿瘤免疫的信息交流中发挥着重要作用^[19]。菌群失衡除了会弱化免疫导致肿瘤易感外, 还会抑制抗肿瘤药物的疗效。环磷酰胺是最为传统的抗肿瘤药之一, 其代谢后产生的氮芥类物质影响DNA合成进而发挥细胞毒作用。然而研究发现, 环磷酰胺能引起肠道革兰阳性菌(乳酸菌、肠球菌)移位至二级淋巴器官, 激活机体产生致病性的辅助性T细胞17, 进而激活抗肿瘤免疫, 缺乏肠道菌群的荷瘤小鼠则对环磷酰胺不敏感^[20]。此外, 肠道菌群还参与抗肿瘤治疗毒副反应的发生, 如肠内拟杆菌丰度与患者对伊匹单抗诱发的胃肠炎敏感性相关^[21]。可见菌群失衡是一个多面的概念, 肠内的优势菌群不同, 所引发的反应及后续对肿瘤的影响均不同。

1.3 微环境免疫抑制

微环境免疫抑制是TME的特征之一。细胞毒T淋巴细胞相关抗原4 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4)、PD-1/PD-L1^{[22, 23]}、免疫抑制细胞Treg、MDSC和瘤内血管及吲哚胺2, 3-双加氧酶(indoleamine-pyrrole 2, 3-dioxygenase, IDO)的异常等^[24], 使得微环境成为机体抗肿瘤免疫反应及免疫干预的“黑洞区”, 难以有效杀伤肿瘤细胞。然而, 研究表明, 微环境的免疫抑制很大部分由免疫治疗诱导, 即counter-regulatory。免疫治疗在杀伤肿瘤细胞或激活T细胞的同时, 产生的炎症信号会诱发免疫抑制。因此, 使用药物封锁诱发性的counter- regulatory通路, 或许能减轻免疫逃逸^[25], 这为临床的联合用药提供了机制基础。

1.3.1 微环境免疫调节点

CTLA-4和PD-1/PD-L1是最经典免疫调节点。PD-1和CTLA-4由活化的T细胞表达, 其生理意义是避免过度的免疫反应。抗CTLA-4抗体Yervoy是首个批准用于临床的免疫检查点抑制剂, 它能大量增加具有新抗原识别力的T细胞, 且此类新抗原是肿瘤与宿主共有的。也就是说, 抗CTLA-4抗体或许可以打破免疫系统对于共有抗原的耐受, 使机体能更好地识别低突变的肿瘤^[26]。

PD-1/PD-L1是另一对经典的免疫抑制分子。肿瘤细胞组成性或诱发性的表达PD-L1, 与T细胞上的PD-1结合后, 即可启动T细胞的程序性凋亡。目前已经上市的PD-1/PD-L1药物共有5个, 分别为靶向PD-1的Opdivo和Keytruda及靶向PD-L1的Tencentriq、Imfinzi和Bavencio。其中, Keytruda还被批准用于含有微卫星高度不稳定及碱基错配修复缺陷(MSI-H/DMMR)的所有实体瘤, 这是全球首个以基因背景而非发病部位获批的抗肿瘤药物。研究发现, 有些患者在诊断时没有PD-L1的表达, 却在接受抗CTLA-4治疗后, 对PD-1抑制剂敏感^[27]。可见PD-L1也存在counter-regulatory, 这或可成为临床联合用药的依据。

1.3.2 微环境免疫抑制细胞

Treg (CD4⁺CD25⁺FoxP3⁺)是微环境免疫抑制细胞之一。损耗Treg或抑制其信号通路, 均能恢复机体对于肿瘤的免疫监视^{[25, 28]}。现有研究表明, FICZ/AhR轴促使树突细胞(dendritic cells, DC)产生IDO, 而IDO能直接刺激Treg的活化^{[29, 30]}; Sema-4a/Nrp-1轴维持Treg的活性及功能^[31]。IL-21/mTOR信号轴则参与Treg的失活^[32]。在Treg存在下, DC缺乏共刺激因子, 以至于无法激活T细胞^[33], 此外Treg还能分泌IL-10和TGF-β等抑制因子。微环境的另一免疫抑制细胞MDSC则可以产生活性氮类化合物(reactive nitrogen species, RNS)硝化趋化因子CCL2, 从而导致T细胞滞留于基质中, 无法靠近肿瘤细胞^[24]。

1.3.3 瘤内血管及IDO异常

瘤内血管参与免疫抑制, 表现为抑制T细胞的瘤内浸润。现有的机制表明, 相比于正常的血管, 瘤内血管高表达凋亡配体FasL, 与循环T细胞表面的凋亡受体FasR结合后, 诱导T细胞的凋亡。然而, 由于Treg细胞表面高表达FLICE抑制蛋白(cellular FLICE inhibitory protain, c-FLIP), 使其能躲避血管的选择性杀伤^[34]。

IDO是微环境中的一类代谢酶, 它可由DC、MDSC或肿瘤细胞共同产生。另有研究表明, M-CSF激活的M2型巨噬细胞, 能分泌大量IDO^[13]。IDO可将微环境中色氨酸代谢为犬尿素。而该代谢对包括CD8⁺ T细胞、自然杀伤细胞(natural killer cells, NK)及自然杀伤T细胞(natural killer T cell, NKT)在内的多种效应细胞具有细胞毒作用, 并同时刺激未成熟T细胞向Treg分化^[35] (图 2)。

2 微环境与转移

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肿瘤相关死亡原因, 首属转移。转移过程可分为: ①脱落并侵袭胞外基质(extracellular matrix, ECM); ②进入血管并在循环系统中存活; ③滞留于远处靶器官; ④穿出血管、定植、启动增殖并形成转移灶^[36]。缺氧参与的原发瘤中癌细胞免疫逃逸, 是转移的首要步骤。如缺氧会增强肿瘤对细胞毒性T细胞诱导的裂解的抵抗; 上调癌细胞表面CD47的表达, 与巨噬细胞表面信号调节蛋白α (signal regulatory protein α, SIRPα)作用后阻止吞噬; 增加胞外腺苷, 与T细胞表面腺苷受体A2A作用后, 抑制T细胞增殖和细胞因子的分泌^[2]。

“种子−土壤”学说认为, 在肿瘤发生转移之前, 原发瘤已经通过自身产生的细胞因子对靶器官进行改造, 使其更适合癌细胞的定植。Premetastatic niche的塑造, 缺氧信号功不可没。缺氧经HIF信号, 增加赖氨酰氧化酶(lysyl oxidase, LOX)及其受体LOXL2/4的表达, 改造肺部胶原基质, 募集髓系细胞(bone marrow-derived cells, BMDC)至肺部, 刺激癌细胞穿出血管^[37]。HIF通路调节癌细胞分泌IL-6, 对转移前微环境中的淋巴管进行改造, 使其大量表达CXCL12, 从而募集CXCR4⁺的癌细胞形成淋巴管转移^[38]。HIF下游的蛋白, 包括基质金属蛋白酶-8/9 (matrix metalloproteinases-8/9, MMP8/9)、PDGF、纤溶酶原激活物抑制剂-1 (plasminogen activator inhibitor-1, PAI-1)及胰岛素生长因子结合蛋白-3 (insulin growth factor binding protein-3, IGFBP-3)等, 可以由外泌体携带至转移前微环境中, 从而增加血管渗透性和BMDC的募集^[39−41]。

癌细胞在靶器官的定植, 同样受到缺氧信号的调控。结肠癌细胞经门脉循环到达肝脏时, 会经历缺氧刺激, 诱导癌细胞高表脑型肌酸激酶(creatine kinase brain-type, CKB), 产生磷酸肌酸供能以适应缺氧, 完成定植^[42]。乳腺癌肝转移时, 经HIF通路激活丙酮酸脱氢酶-1 (pyruvate dehydrogenase kinase-1, PDK1), 抑制细胞的三羧酸循环, 促使细胞以糖酵解供能, 以适应缺氧微环境^[43]。可见, 缺氧参与转移的多个步骤, 以HIF信号通路上的蛋白为靶点, 是一个值得期待的领域。

3 微环境的临床价值

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3.1 实体瘤微环境与CAR-T疗法

2017年8月, FDA批准诺华的Kymriah用于B系急性淋巴细胞白血病的治疗, 使得发展了近30年的嵌合抗原受体−T细胞疗法(chimeric antigen receptors, CAR-T)有了实质性的进展。相比之下, CAR-T在实体瘤领域进展缓慢。目前报道的较为成功的案例有:靶向神经母细胞瘤的GD2 CARs (3/11痊愈)、靶向肉瘤的Her2 CARs (4/17疾病稳定)及靶向肺癌的Her1 CARs (2/11部分缓解), 尚无任何上市产品^[44]。与血液学肿瘤不同的是, CAR-T细胞需要成功进入实体瘤内, 维持其活性及功能, 与肿瘤相关抗原(tumor associated antigens, TAA)相识别, 方能发挥其作用。然而, 该过程存在诸多障碍。首先, 实体瘤的物理屏障会影响CAR-T向瘤内的浸润。其次, 微环境中低氧、低pH、营养不足、各类免疫抑制细胞及其分泌的免疫抑制因子, 会使得成功进入瘤内的CAR-T快速失活。再者, 肿瘤细胞异质性或肿瘤抗原的丢失, 使得CAR-T无法识别而难以激活其细胞毒作用, 最终导致疗效不佳, 甚至因为CAR-T本身的免疫原性而产生毒副作用。

实体瘤的物理屏障, 主要是由肿瘤相关成纤维细胞(FAP⁺ CAFs)导致的。FAP⁺ CAFs分泌大量纤连蛋白及胶原, 构成稠密的肿瘤基质, 使得T细胞在其中几乎丧失移动能力。减少CAFs的数量或者酶解胞外基质可以改善CAR-T的瘤内浸润。目前关于FAP CAR-T及分泌肝素酶的CAR-T的研究均获得了一定的进展^{[45, 46]}。微环境免疫抑制因子TGF-β, 会促使机体免疫反应向Th2型漂移, 也能直接抑制T_eff的功能。定向或系统性地抑制TGF-β能改善CRA-T的疗效。TGF-β受体阴性的CAR-T能抵抗TGF-β的抑制作用, 且其疗效在动物模型中获得了肯定^[47]。抗原异质性是多数实体瘤的通病, 瘤内细胞TAA表达差异使得CAR-T无法消除所有的肿瘤细胞, 影响最终疗效。从理论上说, CAR-T在识别肿瘤细胞后, 会分泌一些刺激因子(例如TNF或IFN-γ)来完成杀伤。死亡的肿瘤细胞释放某些非CAR-T靶点的肿瘤抗原, 进一步被DC提呈后便可由机体本身的CD8⁺ T细胞清除。然而, 由于至今尚未明确肿瘤需要表达多少抗原才能激活上述反应, 因此该理论尚未得到任何验证^[42]。同时靶向多个肿瘤抗原也是解决抗原异质性的途径之一, 包括一种CAR-T同时表达多个抗原或同时给予两种靶点不同的CAR-T, 但目前亦未证实其疗效^[48]。

3.2 微环境生物标志物

生物标志物可以指证疾病的进程或预测治疗的效果, 需要具备灵敏性、特异性、稳定性、精确性及重现性。研究表明, 微环境中多个成分具有生物标志物的潜力。如FAP-α是由活化的成纤维细胞表达的一类膜蛋白。正常情况下只在伤口愈合时才会高表达。然而, 该蛋白在超过90%的肿瘤中高表达, 且与胃癌的病理分型、分期及患者生存率低下相关^[49]。微环境内各类免疫细胞的亚型、数量与疾病的进展相关。Th17和CD8⁺ T/Treg的比例, 与肾透明细胞癌患者的高生存率相关; 而Th2和Treg则与预后不良相关^[50]。类似的, 乳腺癌辅助治疗后, 瘤内CD68⁺ TAM越多, 无病生存期预后越差^[51]。脂肪组织炎症与乳腺癌及舌癌患者的不良预后相关, 巨噬细胞包围死亡的脂肪细胞所形成的冠状结构(crown-like structures, CLS)则可指证组织炎症程度, 进而筛选乳腺癌高危人群^[52]。

3.3 微环境靶点及潜在的药物联用策略

克服TME的免疫抑制, 增加T细胞的数量及瘤内浸润, 是免疫疗法发展的关键点之一。TME中存在多类靶点, 如阻断瘤内血管FasL、内皮素B受体(endothelin receptor type B, ET_BR), 可以抑制瘤内异常血管对循环T细胞的选择性杀伤, 促进其对血管的黏附及瘤内浸润^[34], 联合CAR-T或免疫检查点抑制剂, 或能改善疗效。肿瘤在化疗后会产生DAMPs, 激活DC细胞分泌IL-12, 促进T细胞增殖及对肿瘤的杀伤。但是, 与此同时, 肿瘤源性的M-CSF刺激巨噬细胞释放IL-10来抑制DC, 从而阻断IL-12的释放^[53]。因此, 化疗的同时, 靶向巨噬细胞M-CSFR或DC细胞IL-10R, 以促进T细胞的增殖, 增强化疗疗效。CCR2⁺ MDSC抑制淋巴结内的T_eff向瘤内聚集。转基因手段抑制CCR2, 联合过继细胞疗法(adoptive cell transfer, ACT)或PD-1/PD-L1, 可以增强二者的疗效。FAP⁺ CAF分泌CXCL12能包装癌细胞, 使其类似于受损的表皮细胞, 避免CXCR4⁺ T细胞识别。阻断CXCL12/CXCR4通路, 可以促进T细胞对癌细胞的识别杀伤。已有文献^[54]证明, CXCR4抑制剂Bicyclams联合PD-L1, 可增强后者的疗效。IDO是瘤内存在counter-regulatory一大证明, 它由激活的免疫反应诱发, 以避免过度的免疫反应。因此, 以激活机体免疫为目的的肿瘤免疫治疗, 都应将counter- regulatory考虑在内。IDO抑制剂(如1-甲基色氨酸)能抑制IDO的活性, 弱化counter-regulatory, 联用免疫治疗, 或能改善疗效。表 1罗列了目前Cortellis数据库(https://www.cortellis.com/intelligence/login.do)登记的基于上述靶点及机制发挥药效且已进入临床阶段的药物。此外, 以纳米技术递送药物至瘤内的靶向递药系统也在快速发展^[55]。可见, TME是新药研发不能忽视的领域。

4 展望

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肿瘤微环境自提出至今, 已近40年。大量研究表明, 其作为肿瘤细胞所处的内环境, 对肿瘤的发生、发展及转移均有重要作用。目前的研究成果均能证明, TME中的各类机制相互交叉, 形成一个复杂的机制网络, 共同影响肿瘤的发展。作为一个综合系统, 人们对其的开发尚不能灵活应用于临床。未来, 研究者需要进一步明确微环境在促进肿瘤发展过程中所涉及的机制, 机制针对性地研发新药; 与此同时, 阐明微环境在抗肿瘤治疗中所产生的负面影响, 采用联合用药等方式进行抵抗, 确保治疗的有效性。揭示微环境对于肿瘤发展和治疗的影响, 必将成为一大重要研究领域。

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2018年第53卷第5期

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doi: 10.16438/j.0513-4870.2017-1233

接收时间：2017-12-08
首发时间：2026-01-15
出版时间：2018-05-12

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收稿日期：2017-12-08
修回日期：2018-01-22

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1.中国药科大学, 江苏省新药筛选重点实验室, 江苏南京 210009

2.天士力医药集团股份有限公司创新中药关键技术国家重点实验室, 天津 300410

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* 袁胜涛, Tel:86-25-83271043, E-mail:Yuanst@cpu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Target	Target based action	Drug name	Active indication	Highest status	Drug ID
IL-10R	IL-10 antagonist	MK-1966	Metastasis	Ph 1 clinical	97334
CSF-1R	CSF-1 antagonist	BLZ-945	Advanced solid tumor	Ph 2 clinical	65977
		SNDX-6352	Advanced solid tumor; cancer	Ph 1 clinical	102739
CSF-1R	CSF-1 antagonist	Emactuzumab	solid tumor	Ph 1 clinical	75408
		IMC-CS4	Cancer; stage Ⅳ melanoma	Ph 2 clinical	65181
		Pexidartinib	Colorectal tumor; glioblastoma	Ph 3 clinical	62957
		AMG-820	Cancer	Ph 2 clinical	65242
		PLX-73086	Giant cell bone tumor	Ph 1 clinical	63157
		Cabiralizumab	Cancer; giant cell bone tumor	Ph 2 clinical	72330
		Sunitinib	Adrenal cortical carcinoma	Launched	12973
		ARRY-382	Advanced solid tumor; NSCLC	Ph 2 clinical	67654
		Masitinib	Melanoma; metastatic breast cancer	Pre-registration	57062
CCR2	CCR2 chemokine antagonist	Plozalizumab	Melanoma	Ph 1 clinical	37472
		PF-4136309	Pancreas tumor	Ph 2 clinical	57818
		BMS-813160	Advanced solid tumor	Ph 2 clinical	58959
		CCX-872	Glioma pancreas tumor	Ph 2 clinical	76959
		Propagermanium	Pancreas tumor	Launched	9896
		Emapticap pegol	Acute myelogenous leukemia	Ph 2 clinical	55127
CXCR4	CXCR4 chemokine modulator	USL-311	Glioblastoma; solid tumor	Ph 2 clinical	69745
		Balixafortide	Cancer; stem cell transplantation	Ph 2 clinical	53573
		Burixafor	Leukemia	Ph 2 clinical	59806
		BL-8040	AML; metastatic pancreas cancer	Ph 2 clinical	61169
		Plerixafor	CLL; glioma; non-Hodgkin lymphoma	Launched	16758
		LY-2510924	Acute myelogenous leukemia	Ph 1 clinical	64322
		GMI-1359	Cancer; inflammatory disease	Ph 1 clinical	75115
		F-50067	Cancer	Ph 1 clinical	69148
		Ulocuplumab	AML; advanced solid tumor	Ph 2 clinical	61526
		PF-06747143	AML	Ph 1 clinical	94079
		X4P-001	Melanoma; renal cell carcinoma	Ph 3 clinical	100250
IDO	IDO inhibitor	Navoximod	Solid tumor	Ph 1 clinical	75832
		Indoximod	AML; brain tumor; hormone refractory	Ph 2 clinical	56777
		Epacadostat	Advanced solid tumor; bladder cancer;	Ph 3 clinical	62577
		NLG-802	Cancer	Ph 1 clinical	105484
IDO	IDO inhibitor	BMS-986205	Cancer; hematological neoplasm	Ph 2 clinical	94239
		PF-06840003	Glioma	Ph 1 clinical	78916
		KHK-2455	Advanced solid tumor	Ph 1 clinical	103225
		IO-101	Metastatic non-small cell lung cancer	Ph 2 clinical	101878

Target

Target based action

Drug name

Active indication

Highest status

Drug ID

IL-10R

IL-10 antagonist

MK-1966

Metastasis

Ph 1 clinical

97334

CSF-1R

CSF-1 antagonist

BLZ-945

Advanced solid tumor

Ph 2 clinical

65977

SNDX-6352

Advanced solid tumor; cancer

Ph 1 clinical

102739

CSF-1R

CSF-1 antagonist

Emactuzumab

solid tumor

Ph 1 clinical

75408

IMC-CS4

Cancer; stage Ⅳ melanoma

Ph 2 clinical

65181

Pexidartinib

Colorectal tumor; glioblastoma

Ph 3 clinical

62957

AMG-820

Cancer

Ph 2 clinical

65242

PLX-73086

Giant cell bone tumor

Ph 1 clinical

63157

Cabiralizumab

Cancer; giant cell bone tumor

Ph 2 clinical

72330

Sunitinib

Adrenal cortical carcinoma

Launched

12973

ARRY-382

Advanced solid tumor; NSCLC

Ph 2 clinical

67654

Masitinib

Melanoma; metastatic breast cancer

Pre-registration

57062

CCR2

CCR2 chemokine antagonist

Plozalizumab

Melanoma

Ph 1 clinical

37472

PF-4136309

Pancreas tumor

Ph 2 clinical

57818

BMS-813160

Advanced solid tumor

Ph 2 clinical

58959

CCX-872

Glioma pancreas tumor

Ph 2 clinical

76959

Propagermanium

Pancreas tumor

Launched

9896

Emapticap pegol

Acute myelogenous leukemia

Ph 2 clinical

55127

CXCR4

CXCR4 chemokine modulator

USL-311

Glioblastoma; solid tumor

Ph 2 clinical

69745

Balixafortide

Cancer; stem cell transplantation

Ph 2 clinical

53573

Burixafor

Leukemia

Ph 2 clinical

59806

BL-8040

AML; metastatic pancreas cancer

Ph 2 clinical

61169

Plerixafor

CLL; glioma; non-Hodgkin lymphoma

Launched

16758

LY-2510924

Acute myelogenous leukemia

Ph 1 clinical

64322

GMI-1359

Cancer; inflammatory disease

Ph 1 clinical

75115

F-50067

Cancer

Ph 1 clinical

69148

Ulocuplumab

AML; advanced solid tumor

Ph 2 clinical

61526

PF-06747143

AML

Ph 1 clinical

94079

X4P-001

Melanoma; renal cell carcinoma

Ph 3 clinical

100250

IDO

IDO inhibitor

Navoximod

Solid tumor

Ph 1 clinical

75832

Indoximod

AML; brain tumor; hormone refractory

Ph 2 clinical

56777

Epacadostat

Advanced solid tumor; bladder cancer;

Ph 3 clinical

62577

NLG-802

Cancer

Ph 1 clinical

105484

IDO

IDO inhibitor

BMS-986205

Cancer; hematological neoplasm

Ph 2 clinical

94239

PF-06840003

Glioma

Ph 1 clinical

78916

KHK-2455

Advanced solid tumor

Ph 1 clinical

103225

IO-101

Metastatic non-small cell lung cancer

Ph 2 clinical

101878