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结直肠癌（colorectal cancer，CRC）是癌症相关死亡的主要原因之一，其发病率和死亡率分别居全球肿瘤的第三位和第二位[1]。肿瘤微环境（tumor microenvironment，TME）是决定肿瘤发生发展及治疗效果、预后的关键因素，TME主要由肿瘤细胞、浸润性免疫细胞、肿瘤相关成纤维细胞（cancer associated fibroblasts，CAFs）、细胞外基质（extracellular matrix，ECM）和脉管系统等构成[2-4]。在各种TME中，CAFs是最丰富的细胞类型之一，在影响肿瘤恶性表型方面起着极其重要的作用，并且以CAFs作为肿瘤治疗的靶标也逐渐引起了人们的关注。
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人们将TME中的活化成纤维细胞定义为CAFs，其经典的生物学标志物为α-平滑肌动蛋白（α-SMA）和成纤维细胞活化蛋白（FAP）。CAFs是肿瘤基质中的主要组成成分，其作用为分泌生长因子、炎症配体和细胞外基质蛋白，促进肿瘤增殖和免疫抑制[5]。CAFs的主要来源有：1）肿瘤激活邻近的正常成纤维细胞，获得肌成纤维细胞表型[6-8]；2）骨髓源性纤维细胞的募集[9-10]；3）上皮-间质转化（epithelial-mesenchymal transformation，EMT）[11]；4）内皮-间质转化（endothelial-to-mesenchymal transition，EndMT）[12]。
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近年来，人们除了对 CAFs 在促进肿瘤的发生和发展中的作用有了比较深入的认识以外，有关 CAFs 与 TME 中其他免疫细胞之间的相互作用以及对肿瘤免疫治疗的影响也展开了许多研究。本文将就有关 CAFs 对结直肠癌 TME 中主要细胞成分的调节及影响肿瘤免疫治疗的进展研究进行综述。
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1 TIME中免疫细胞浸润是影响肿瘤进展及免疫治疗效果的关键因素
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肿瘤免疫微环境（tumor immune microenvironment，TIME）是近年来新提出的概念，据报道其与患者的免疫治疗效果和临床预后密切相关[13]。目前，随着免疫治疗的发展，治疗恶性肿瘤的方式逐渐多样化，但其发挥效应取决于TME中的免疫应答状态，包括免疫细胞的浸润、细胞表面免疫检查点的表达和相关基质的改变[14-15]。肿瘤实质中缺乏免疫细胞浸润是导致患者不能从免疫治疗中获益的关键因素，进而导致恶性肿瘤的进展[16-17]。
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2 CAFs对结直肠癌TME中T细胞的影响
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在各种类型的免疫疗法中，免疫检查点阻断是基于单克隆抗体的疗法，也是在临床上应用于患者最多的方式之一。临床上常用的免疫治疗有：通过阻断受体-配体相互作用、增强T细胞的活化和功能，例如抗程序性死亡受体1（PD-1）和抗细胞毒性T淋巴细胞抗原4（CTLA-4）。CAFs影响结直肠癌TME中的免疫状态，从而导致抗肿瘤免疫抑制。以下就结直肠癌中CAFs对T细胞调控的具体机制进行阐述。
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参与抗肿瘤免疫的细胞主要是细胞毒性淋巴细胞（cytotoxic lymphocytes，CTLs），而其中起最大杀伤作用的是CD8+T细胞。CAFs通过多种方式影响CD8+T细胞的生物学功能。目前，靶向PD-1/程序性死亡配体1（PD-L1）和CTLA-4的免疫检查点抑制剂在多种恶性肿瘤被应用[18-20]。然而，大多数患者对于检查点单药治疗无响应[21-23]，耐药性产生的原因是全球研究者最为关注的热点之一。对多种肿瘤的研究发现富含CAFs的瘤种对抗PD-1治疗的疗效较差。其机制之一在于CAFs自身表达PD-L1和PD-L2或者促进CRC细胞表面的PD-L3和PD-L1表达，导致CD8+T细胞对癌细胞的杀伤作用减弱[24-26]。另外，CAFs通过限制CD8+T细胞向肿瘤中心浸润来减少免疫细胞对肿瘤的攻击。例如，Ford等[27]在MC38小鼠体内研究发现，与低CAFs的肿瘤相比，富含CAFs的肿瘤对抗PD-1治疗的疗效较差。他们用多种方法检测了免疫细胞的定位，发现CAFs显著改变了CD8+T细胞的分布，促使CD8+T细胞积聚在肿瘤边缘而非肿瘤中心。一项针对CRC患者的研究表明，CD70阳性的CAFs促进了调节性T细胞募集和迁移，并显著增加了这些抑制性免疫细胞对TME的浸润[28]。而另一项研究表示CD70阳性的CRC患者的生存率较差[29]。
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众所周知，转化生长因子-β（TGF-β）是调节CAFs分化的重要因子，而NOX4是TGF-β信号通路下游的靶点之一，并也参与了CAFs分化[30]。反之，CAFs也可促进TGFβ-1的分泌和活化，从而抑制CD8+T细胞的增殖和细胞毒性[31]。同时，CAFs也可以通过PD-L2和FASL的表达诱导CD8+T细胞凋亡[32]。根据Ford等[27]的报道，使用TGF-β抑制剂能同时增加对照组和富含CAFs组的CD8+T细胞浸润，在体内应用NOX4抑制剂后，可以降低肿瘤中CAFs的水平，肿瘤边缘的CD8+T细胞开始由肿瘤边缘向肿瘤中心浸润，从而引起富含CAFs的MC38小鼠肿瘤的体积减小。NOX4抑制能使CRC对抗PD-1治疗再敏感；与抗PD-1单药治疗相比，用NOX4抑制剂/PD-1抗体的组合治疗富含CAFs的MC38肿瘤，可以增加CD8+T细胞的浸润、缩小肿瘤体积，延长小鼠的存活时间。此外，有研究发现CAFs分泌的Wnt2蛋白信号通路相关基因在TGF-β信号传导中高度富集，从而加强了CRC的侵袭和迁移。[33]
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FAP是一种膜结合丝氨酸蛋白酶，同时其也是CAFs的主要标志物[34]。越来越多的证据表明，FAP是另外一个可能导致免疫检查点阻断耐药的因素[35-37]。Chen等[38]报道，含有FAP高表达CAFs（CAF2）的肿瘤对抗PD-1治疗的反应较差，而FAP低表达的CAFs则不会诱导肿瘤产生抗PD-1的耐药性。另外，用FAP抑制剂治疗可显著消除CAF2诱导的抗PD-1耐药性。在富含CAF2的肿瘤中，免疫抑制因素，如骨髓来源抑制细胞（MDSC）浸润和PD-L1表达异常升高。高FAP表达的CAFs通过上调CCL2分泌、募集髓系细胞、降低T细胞活性等方式促进CRC肿瘤免疫微环境中的免疫抑制[38-39]。上述研究表明CCL2是FAP高表达CAFs诱导的CRC免疫抑制的主要介质，生存分析发现高FAP表达患者的总生存期较短。另有研究提示FAP高表达的CAFs分泌的ECM与CD8+T细胞浸润减少有关[40-41]。
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CD73是一种外核苷酸酶，通过与外核苷-ATP-酶、CD39等协同产生细胞外腺苷（ADO）[42-44]。腺苷是TME中一种有效的细胞外免疫抑制信使[45]，通过细胞外ADO腺苷能受体（A2a）施加免疫抑制[46-47]。已有研究发现CD73在肿瘤中的过表达通过增强肿瘤细胞的侵袭性和抑制抗肿瘤免疫来促进肿瘤进展，而TME中CD73的重要来源之一是CAFs。Yu等[48]使用来自人CRC和小鼠肿瘤模型中分离出来的CAFs进行比较，发现与TME中的其他细胞成分相比，CD73在CAFs上的表达和生物活性更高。在缺氧等应激条件下，CD73与其他外核苷酸酶（如CD39）一起产生高浓度的ADO，通过与其激活的受体A2a结合，影响肿瘤细胞和免疫细胞中的生物途径，从而影响肿瘤进展和免疫抑制[49]。而CRC中的A2a受体在T细胞上表达，由ADO激活后产生肿瘤免疫抑制作用。反之，TME中ADO升高还可以通过A2b受体介导的途径上调CAFs上的CD73，从而刺激ADO-A2b-CD73回路，进一步增强免疫抑制。人结直肠癌TME中高水平的CD73表达与CAFs丰度，增强免疫抑制和预后不良呈正相关[48]。此外，有研究提示CAFs可上调T细胞上的CD39表达，而T细胞反过来上调CAFs上的CD73的表达，由此加重抗肿瘤免疫抑制[50]。
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CAFs还通过分泌大量含胶原蛋白的ECM来调节的免疫细胞锚定和运输、存活以及通过抑制免疫激活促进肿瘤的进展[51-53]。在含有密集堆积基质纤维的基质区域中，淋巴细胞位移减少，支持了ECM沉积可能通过限制T细胞运动来改变抗肿瘤免疫反应的观点[54]。由于ECM大量堆积使肿瘤中心含氧量减少从而导致CAFs激活，产生上述CAFs影响免疫细胞的机制，进一步促进免疫抑制[55-56]。总之，CAFs通过自身表达和分泌一致性免疫检查点相关分子，以及促进肿瘤细胞表达免疫抑制物来促进CRC免疫逃逸。
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3 CAFs对巨噬细胞、NK细胞及其他细胞的影响
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肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）作为TME的重要成分在调节抗肿瘤免疫反应中起着关键作用。TAMs在肿瘤微环境中存在两种表型，分别执行不同的功能。M1巨噬细胞能通过激活免疫系统、产生肿瘤坏死因子产生抗肿瘤作用，而M2巨噬细胞通过分泌免疫抑制因子发挥免疫抑制和促进肿瘤作用[40，57]。CAFs通过各种机制诱导单核细胞在CRC中募集并分化为M2巨噬细胞：首先，CAFs通过白细胞介素（IL）-8/CXCR2途径吸引单核细胞浸润至CRC中，并通过上调结直肠癌细胞中的VCAM-1表达和CAFs的IL-6分泌来促进单核细胞与CRC黏附；其次，癌细胞介导CAFs分泌IL-6和GM-CSF诱导单核细胞向M2巨噬细胞分化，促使CRC侵袭能力增加，导致CRC患者的预后不佳[58-59]。巨噬细胞与CAFs协同抑制自然杀伤（NK）细胞的功能，保护CRC细胞免受NK细胞介导的杀伤 [57]。
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NK是浸润到TME中的免疫细胞之一，对癌细胞有杀伤作用[60-61]。CAFs分泌的TGF-β可以抑制NK细胞的活化和细胞毒性[62-63]，CAFs还可产生高水平的促炎细胞因子PGE2，并且通过多种机制调节NK细胞的功能[64-66]。Li等[67]从结直肠癌标本中提取CAFs细胞，并与NK细胞共培养，发现CAFs产生高水平的PGE2，可以通过多种方式影响NK细胞的功能，从而产生免疫抑制，包括NK受体活化，细胞毒性活性和细胞因子产生。CAFs诱导的M2巨噬细胞可抑制NK细胞对癌细胞的杀伤功能，说明TAMs和CAFs在肿瘤微环境中发挥协同作用，CAFs可以通过其他免疫细胞调节NK细胞的功能[59]。另有研究表示，在CRC中使用表皮生长因子受体（EGFR）抗体可以抵消CAFs对NK细胞的抑制作用[68]。
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中性粒细胞最初是在炎症和损伤修复中发现。近年来有研究发现肿瘤相关中性粒细胞（tumor associated neutrophils，TANs）亦是TME的重要组成成分，并促进肿瘤的生长、侵袭和转移[69-70]。TANs参与先天性和适应性免疫调节，并受环境影响可分化为2种不同表型，即N1抗肿瘤亚型和N2促肿瘤亚型中性粒细胞[71-72]。N1和N2之间的可塑性通过TGF-β和干扰素-β信号传导调节，如CAFs通过分泌TGF-β来诱导N2极化，抑制TGF-β后N1则表达免疫激活因子和趋化因子[73]。在CRC中，通过PGE2/EP信号传导能促进CAFs和TANs的活性，从而对抗肿瘤免疫产生影响[74]。
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4 小结
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综上所述，CRC中的CAFs主要通过以下方式影响抗肿瘤免疫：1）分泌大量ECM限制CD8+T细胞的移动；2）通过TGF-β通路下游的靶点NOX4使肿瘤对抗PD-1耐药，具有FAP高表达的CAFs的肿瘤对抗PD-1耐药，CAFs分泌的CCL2是其中的主要介质；3）CAFs自身表达CD73产生ADO作用于T细胞上的A2a受体产生免疫抑制；4）CAFs可以通过上调结直肠癌细胞中的VCAM-1表达以及分泌IL-6来促进单核细胞与CRC肿瘤细胞的黏附，并诱导M2型巨噬细胞的极化。CAFs和M2协同抑制NK细胞的功能。以上内容表明，CAFs不仅可通过分泌多种细胞因子或代谢产物抑制免疫细胞的功能，促进肿瘤的发生发展，同时还可以塑造肿瘤外基质阻止药物及免疫细胞向肿瘤组织的深层渗透，从而降低抗肿瘤的治疗效果。未来在临床有望可以通过对CAFs的干预，联合免疫治疗对结肠癌患者的治疗带来新思路。
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摘要
结直肠癌（CRC）是全球癌症死亡的第二大原因，常规的治疗手段并未明显降低其死亡率。近年来，免疫治疗给许多肿瘤患者带来了新希望。但是，大多数CRC患者对免疫治疗缺乏响应，耐药的关键机制之一在于肿瘤微环境（TME）中各类细胞间的相互作用，导致肿瘤抑制性免疫微环境的形成。肿瘤相关成纤维细胞（CAFs）是TME中重要的组成部分，在CRC的发生、发展及免疫治疗抵抗中扮演了重要角色。该文拟对近年来有关CAFs通过调节CRC微环境中免疫细胞促进肿瘤产生免疫逃逸和免疫治疗抵抗机制的研究进行综述，为靶向CAFs、提高CRC免疫治疗疗效提供理论依据。