肿瘤相关巨噬细胞在晚期卵巢癌组织中的浸润与肿瘤浸润淋巴细胞表型、免疫效能之间的关系

Relationship between invasion of tumor-associated macrophages and phenotype and immune efficacy of tumor-infiltrating lymphocytes in advanced ovarian carcinoma

目的:探讨晚期卵巢癌组织中浸润的肿瘤相关巨噬细胞(tumor-associated macrophage,TAM)与肿瘤浸润淋巴细胞(tumor-infiltrating lymphocyte,TIL)表型及免疫效能的关系。方法:免疫组化方法分析175例低分化卵巢癌组织病理切片中TAM分布密度,以中位数为界限将病例分为TAM高密度组和TAM低密度组,对照组为32例良性卵巢病变组织;应用流式细胞术分析TAM高密度组与TAM低密度组中TIL的CD8+和CD25+表型变化情况;体外扩增培养TIL后取细胞培养上清液,ELISA法分析各组TIL中白细胞介素2(IL-2)、白细胞介素-10(IL-10)、转化生长因子β(TGF-β)和干扰素γ(IFN-γ)细胞因子表达变化。结果:175例低分化卵巢癌组织中TAM平均浸润密度为62.8/高倍镜视野(HP,×400),中位数为53.3/HP,其中TAM高密度组87例,TAM低密度组88例;对照组TAM平均浸润密度10.5/HP(P<0.05)。CD8+在TAM高密度组中表达平均值为24%,在TAM低密度组中表达平均值为52%(P<0.05);CD25+在TAM高密度组中表达平均值为48%,在TAM低密度组中表达平均值为25%(P<0.05);对照组中CD8+和CD25+的TIL平均浸润密度为7%,TAM高密度组及TAM低密度组中CD8+和CD25+的TIL平均浸润密度显著高于对照组(P<0.05)。与TAM低密度组比较,TAM高密度组中TIL的杀伤性细胞因子IL-2和IFN-γ表达明显减少(P<0.05),而抑制性细胞因子IL-10和TGF-β表达明显增加(P<0.05)。结论:高密度TAM浸润的卵巢癌组织中,CD25+的TIL表型增多,CD8+的TIL表型减少,抑制性细胞因子IL-10和TGF-β表达增加,杀伤性细胞因子IL-2和IFN-γ表达减少,提示TAM浸润密度与TIL表型及免疫效能相关。

AIM：To explore the relationship between the invasion of tumor-associated macrophages（TAM） and the phenotype and immune efficacy of tumor-infiltrating lymphocytes（TIL） in advanced ovarian carcinoma. METHODS：Immunohistochemical analysis of TAM density in 175 cases of poorly-differentiated ovarian cancer tissue biopsy was performed. The cases were divided into TAM high-density（TAMHigh） group and TAM low-density（TAMLow） group according to the median of TAM density. The control group included 32 cases of benign ovarian lesions. The changes of CD8＋ and CD25＋ phenotypes of TIL were detected by flow cytometry analysis. TIL in the 2 groups were cultured in vitro and the conditioned-medium was collected for detecting the expression of IL-2, IL-10, TGF-β and IFN-γ by ELISA. RESULTS：The average TAM infiltration density was 62.8/high-power field（HP, ×400） in 175 cases of poorly-differentiated ovarian carcinoma, and the median was 53.3/HP. TAMHigh group was 87 cases and TAMLow group was 88 cases. A significant difference between malignant ovarian carcinoma group and control group（10.5/HP） was observed. The mean expression of CD8＋ TIL in TAMHigh group was 24%, and CD8＋ TIL in TAMLow group was 52%（P〈0.05）. The mean expression of CD25＋ TIL in TAMHigh was 48%, and CD25＋ TIL in TAMLow was 25%（P〈0.05）. The average infiltration density of CD8＋ and CD25＋ TIL in control group was 7%. The average infiltration density of CD8＋ and CD25＋ TIL in TAMHigh and TAMLow groups was significantly higher than that in control group（P〈0.05）. Compared with TAMLow group, TIL destruction cytokines IL-2 and IFN-γ were significantly decreased in TAMHigh group（P〈0.05）, while the inhibitory cytokines IL-10 and TGF-β were significantly increased（P〈0.05）. CONCLUSION：In high-density TAM infiltration of ovarian cancer tissues, CD25＋ TIL type and inhibitory cytokines IL-10 and TGF-β increase, while CD8＋ TIL type and destruction cytokines IL-2/IFN-γ decrease, suggesting that the high-density TAM has relationship with the phenotype and immune efficacy of TIL.