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结直肠癌(Colorectal cancer, CRC)是一种进行性癌症,其增殖、迁移和转移过程十分复杂,涉及诸多因素和信号通路,死亡率居高不下。肿瘤微环境(tumor microenvironment, TME)是由各种细胞以及其分泌的蛋白质、细胞因子、趋化因子和外泌体等组成的独特体系[1]。TME中的巨噬细胞即为肿瘤相关巨噬细胞(tumor-associated macrophage,TAMs),是TME最主要的免疫细胞。越来越多研究发现,TAMs具有肿瘤促进作用,然而其在CRC中的作用及其机制尚不完全清楚,因此,我们有必要就TAMs的来源、表型极化及其在CRC TME中的作用及其机制进行综述,探讨针对TAMs的相关免疫治疗CRC的策略,总结不同亚型的TAMs对CRC的预后评估价值,从而为临床治疗CRC提供新思路。
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TAMs是高度异质性巨噬细胞,其表型和功能具有可塑性。在肿瘤中,巨噬细胞主要起源于骨髓前体细胞分化的单核细胞(M0型TAMs)。单核细胞迁移出血管后可诱导为M1型TAMs(由经典途径激活)和M2型TAMs(由替代途径激活)[2]。通常,使用不同的标志物来鉴定CRC中的TAMs,包括最常见的泛TAMs标志物CD68;M1型TAMs标志物,如一氧化氮合酶(inducible nitric oxide synthase, iNOS)、CD86和CD169;M2型TAMs标志物,如CD163、CD206和CD204。作为TME的一员,TAMs的生物活性会受到TME中不同化学物质的影响。TME中的干扰素-γ(interferon-γ, IFN-γ)、脂多糖(lipopolysaccharide, LPS)、肿瘤坏死因子α(tumor necrosis factor α, TNF-α)、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor, GM-CSF)等可诱导M1型TAMs活化[3-4]。活化的M1型TAMs分泌iNOS、活性氧(reactive oxygen species, ROS)和促炎细胞因子如白细胞介素(interleukin, IL)-6、IL-12、TNF-α[5-8]等,使M1型TAMs能够杀死病原体并引发抗肿瘤免疫反应。然而,TME中的某些物质也可诱导M2型TAMs活化,根据不同的活化物质,可将M2型TAMs进一步分为四种不同的亚型,即M2a(由IL-4、IL-13诱导)、M2b(由免疫复合物诱导)、M2c[由IL-10、转化生长因子β (transforming growth factor β, TGF-β)和糖皮质激素诱导]和M2d(由IL-6和腺苷诱导)[9]。活化的M2型TAMs可分泌可溶性因子,如IL-6、TGF-β1、血管内皮生长因子(vascular endothelial growth factor, VEGF)、精氨酸酶1、C-C基序趋化因子(C-C motif chemokine, CCL)22、趋化因子(chemokine, CXCL)12和CXCL13等发挥肿瘤促进作用[10-15],具体分泌的可溶性因子及促肿瘤结果见表 1。事实上,巨噬细胞的极化状态是非常复杂的,有的巨噬细胞同时具有M1和M2的特征。但在CRC TME中的TAMs主要表现为M2型,通过促进CRC血管生成、转移、改变CRC耐药性和促进CRC免疫逃逸等发挥促肿瘤作用。CRC中TAMs的来源、表型极化及其在TME中的作用见图 1。
TAMs分泌的可溶性因子 促肿瘤结果 IL-1、IL-8、VEGF、TNF-α、MMPs 血管生成 IL-6、TGF-β1、VEGF、CXCL12、CXCL13、MMPs、组织蛋白酶、丝氨酸蛋白酶 肿瘤转移 CCL22、VEGF、腐胺 抗肿瘤治疗耐药性 TGF-β、精氨酸酶1、前列腺素E2、外泌体miR-155-5p 免疫逃逸 表 1 TAMs分泌的可溶性因子及其各种促肿瘤结果
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在CRC发生发展中,TAMs的作用十分复杂,并且越来越多研究发现,TAMs与CRC病人预后相关。有研究者称TAMs与更好的CRC病人预后相关,另一些研究者认为,TAMs与不良预后相关。TAMs与CRC病人预后的相关文献汇总见表 2。
研究结果 TAMs表达式 样本量(n) 参考文献 良好预后 CRC基质中高密度的CD68+TAMs与病人良好的5年总生存率显著相关 高密度CD68+ 6 115 [2] CRC组织中高密度的CD86+TAMs与总生存期呈正相关,且与肿瘤分化和肿瘤转移分期呈显著负相关 高密度CD86+ 64 [43] 移分期呈显著负相关 CRC基质中较高的M1∶M2密度比与更好的癌症特异性生存率相关 高M1/M2比 931 [44] 辅助化疗显著改善了TAMs中CD206+/CD68+比值高的Ⅱ期CRC病人的无病生存率和5年生存率 高CD206+/CD68+比 835 [45] 不良预后 CRC上皮内CD68+TAMs数量增加与病人短的总生存期和无进展生存期呈正相关 高密度CD68+ 584 [46] 高密度CD163+TAMs浸润与CRC病人的预后不良有关 高密度CD163+ 209 [47] 在肿瘤中心中高密度的M2型TAMs与CRC病人的生存不良相关 高M2 5 575 [48] Ⅱ~Ⅲ期CRC基质中低CD86+/CD163+比与更短的无复发生存期和总生存期相关 低CD86+/CD163+比 449 [49] 表 2 TAMs与CRC病人预后的相关文献报道
不同类型和位置的TAMs对CRC病人具有不同的预后意义。有研究[2]发现,CD68作为泛TAMs的表面标志物,在CRC基质中高密度的CD68+TAMs与良好预后相关;而在CRC上皮内CD68+TAMs数量增加却与不良预后相关[46]。可见,TAMs总密度并不能作为CRC的预后评估,而TAMs的不同极化状态表现出不同的预后作用。如CRC组织中高密度的CD86+TAMs与总生存期呈正相关,且与肿瘤分化和肿瘤转移分期呈显著负相关[43];而高密度的CD163+TAMs和M2型TAMs与病人不良预后相关[47]。另外,不同亚型的TAMs比值对CRC预后也有预测价值。有研究发现,CRC基质中较高的M1∶M2密度比与更好的癌症特异性生存率相关[44];而低CD86+/CD163+比与CRC病人更短的无复发生存期和总生存期相关[49];并且,对于Ⅱ期CRC,CD206+/CD68+比值可作为术后辅助化疗的更好预后和预测性生物标志物[45]。这些发现表明,是不同亚型的TAMs及其比值,而不是其总体密度,可作为CRC的预测性生物标志物和预后危险因素。
肿瘤相关巨噬细胞在结直肠癌发展及治疗和预后中的作用
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表 1 TAMs分泌的可溶性因子及其各种促肿瘤结果
TAMs分泌的可溶性因子 促肿瘤结果 IL-1、IL-8、VEGF、TNF-α、MMPs 血管生成 IL-6、TGF-β1、VEGF、CXCL12、CXCL13、MMPs、组织蛋白酶、丝氨酸蛋白酶 肿瘤转移 CCL22、VEGF、腐胺 抗肿瘤治疗耐药性 TGF-β、精氨酸酶1、前列腺素E2、外泌体miR-155-5p 免疫逃逸 表 2 TAMs与CRC病人预后的相关文献报道
研究结果 TAMs表达式 样本量(n) 参考文献 良好预后 CRC基质中高密度的CD68+TAMs与病人良好的5年总生存率显著相关 高密度CD68+ 6 115 [2] CRC组织中高密度的CD86+TAMs与总生存期呈正相关,且与肿瘤分化和肿瘤转移分期呈显著负相关 高密度CD86+ 64 [43] 移分期呈显著负相关 CRC基质中较高的M1∶M2密度比与更好的癌症特异性生存率相关 高M1/M2比 931 [44] 辅助化疗显著改善了TAMs中CD206+/CD68+比值高的Ⅱ期CRC病人的无病生存率和5年生存率 高CD206+/CD68+比 835 [45] 不良预后 CRC上皮内CD68+TAMs数量增加与病人短的总生存期和无进展生存期呈正相关 高密度CD68+ 584 [46] 高密度CD163+TAMs浸润与CRC病人的预后不良有关 高密度CD163+ 209 [47] 在肿瘤中心中高密度的M2型TAMs与CRC病人的生存不良相关 高M2 5 575 [48] Ⅱ~Ⅲ期CRC基质中低CD86+/CD163+比与更短的无复发生存期和总生存期相关 低CD86+/CD163+比 449 [49] -
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