肿瘤相关性巨噬细胞在多发性骨髓瘤中的浸润及其临床意义

Infiltration of tumor associated macrophages in multiple myeloma and its clinical significance

【摘要】目的探讨肿瘤相关性巨噬细胞（TAM）在多发性骨髓瘤（MM）中的临床意义及其与肿瘤血管生成、免疫抑制的关系。方法以2015年8月至2017年6月就诊的70例MM患者为观察对象，以20例良性血液病（缺铁性贫血13例，巨幼细胞性贫血7例）患者为对照，采用免疫组化法检测骨髓标本中CDl63、CD34、VEGF的表达，采用流式细胞术检测Treg细胞比例，采用ELISA法检测IL-10水平，结合临床特征进行分析。结果①70例患者中，男31例，女39例，中位年龄65（50～78）岁。MM患者组的TAM浸润密度、微血管密度（MVD）、VEGF表达水平、Treg细胞比例及IL—10水平均较对照组升高（P值均〈0．05）。②在MM患者组中，疾病稳定组（15例）患者的上述指标均较初诊组（35例）和复发难治组（20例）低（P值均〈0．05）；后两组差异无统计学意义（P值均〉0．05）。③35例初诊MM患者中27例完成4个疗程治疗，有效组（15例）治疗后TAM浸润密度较治疗前明显下降，差异有统计学意义[（20．20±7．66）对（28．87±11．97）个／高倍，t=2．362，P=0．025]；无效组（12例）治疗前后差异无统计学意义[（42．00±13．76）对（48．25±13．59）个／高倍，t=1．119，P=0．275]。④硼替佐米方案治疗有效组患者（21例次）的TAM浸润密度较非硼替佐米方案治疗有效组（18例次）减低[（16．52±4．26）对（19．27±5．82）个／高倍，t=1．662，P=0．170]。@MM患者的TAM浸润密度与MVD、VEGF表达水平、Treg细胞比例及IL．10水平呈正相关（P值均〈0．001）。结论骨髓微环境中浸润的TAM与MM发生、发展、疗效及治疗耐药有关，其作用机制可能与TAM促进肿瘤血管形成及抑制免疫反应有关。

Objective To investigate the clinical significance of tumor associated macrophages （TAM） in multiple myeloma （MM） and the relationship with angiogenesis and immunosuppression. Methods Seventy cases of MM patients diagnosed from August 2015 to June 2017 were enrolled in the study as experimental group, 20 cases of benign hematological diseases （13 with iron deficiency anemia and 7 with megaloblastic anemia） patients as control group. Immunohistochemical method was used to detect the expression of CD163, CD34 and VEGF in bone marrow samples, and flow cytometry was used to detect the proportion of regulatory T cell （Treg cells）, ELISA was used to detect the level of IL-10, and the clinical features were analyzed. Results （1） Among the 70 patients, there were 31 males and 39 females with a median age of 65 （50 - 78） years old. TAM infiltration density, microvascular density （MVD）, VEGF expression level, Treg ratio and IL- 10 level in bone marrow samples of 70 MM patients were significantly higher than those of benign hematological diseases （P 〈 0.05）. （2）In the MM group, the above indexes of the patients with disease stabilized （15 cases） were lower than those of the newly diagnosed group （35 cases） and the relapse refractory group （20 cases） （P〈 0.05）, those of relapse refractory group were higher than those of newly diagnosed group （P 〉 0.05）. （3）Of the 35 newly diagnosed MM patients, 27 completed 4 courses of treatment. In the effective group （15 cases）, the TAM infiltration density after treatment was significantly lower than that before treatment, the difference was statistically significant [（20.20± 7.66） vs （28.87 ± 11.97）, t = 2.362, P = 0.025]; while in the ineffective group of 12 cases, the difference of the TAM infiltration density before and after treatment was not statistically significant [（42.00±13.76） vs （48.25± 13.59）, t= 1.119, P=0.275]. （4）TAM infiltration density in the effective group after bortezomib treatment （21 cases） were lower than those in the non-bortezomib treatment group （18 cases）[ （16.52 ±4.26） vs （19.27 ±5.82）, t = 1.662, P = 0.1701. （5）The TAM infiltration density in MM patients was positively correlated with MVD, VEGF expression level, Treg cell ratio and IL-10 level （P 〈 0.001）. Conclusion The infiltration of TAM in the microenvironment of MM, which may promoting angiogenesis and inhibiting immune response, is related to the occurrence, development, therapeutic effect and drug resistance of MM.