荷瘤小鼠髓系抑制性细胞比例和TGF-β_1表达水平关系的研究
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摘要
目的：研究荷瘤小鼠肿瘤组织及外周血中髓系抑制性细胞(myeloid-derived suppressor cells, MDSCs)的比例变化及其在肿瘤组织中的分布特点,分析外周血中MDSCs与血清转化生长因子β1 (transforming growth factor-β1, TGF-β1)表达水平的关系,探讨其在肝癌免疫逃逸中的意义及作用机制。
方法：建立小鼠原位肝癌模型,于荷瘤7d、14d、21d天取材,流式细胞仪检测荷瘤小鼠肿瘤组织和外周血中MDSCs的比例；免疫组织化学法检测MDSCs在肿瘤组织中的分布情况；酶联免疫吸附试验(enzyme-linked immunosorbent assay, ELISA)检测血清TGF-β1的水平；分析外周血中MDSCs比例与血清TGF-β1水平的相关性,以健康正常小鼠作对照。
结果：
1.正常小鼠肝组织中MDSCs的比例很低,为(1.62+0.82)%,荷瘤7d、14d、21d肿瘤组织中MDSCs的比例分别为(9.12±2.26)%、(14.40±2.87)%、(26.27±8.65)%。正常小鼠外周血中MDSCs的比例为(3.54±2.15)%,荷瘤7d、14d、21d外周血中MDSCs的比例分别为(9.45±2.64)%、(16.40±5.55)%、(25.28±11.32)%。与正常小鼠比较,荷瘤小鼠肿瘤组织和外周血中MDSCs的比例均明显升高(P<0.05),且随着荷瘤时间的延长,MDSCs的比例呈渐进性升高。
2.用anti-Gr-1抗体免疫组织化学法检测荷瘤小鼠肿瘤组织中MDSCs的分布情况,结果显示,正常小鼠肝组织中无或仅有极少量的MDSCs,肿瘤组织中MDSCs主要分布于肿瘤组织与正常组织交界处,且随肿瘤进展MDSCs比例升高。
3.正常小鼠血清TGF-β1水平为(4.89±1.45)ng/ml,荷瘤小鼠7d、14d、21d血清TGF-β1,水平分别为(14.07±6.01) ng/ml、(23.98±3.27) ng/ml、(9.17±1.22) ng/ml,与正常小鼠比较,荷瘤小鼠血清TGF-β1水平明显升高(P<0.05)。
4. Pearson相关分析结果表明：外周血中MDSCs比例与血清TGF-p,水平呈明显正相关(r=0.564,P<0.05)。
结论：随着肿瘤的进展,荷瘤小鼠肿瘤组织和外周血中MDSCs的比例明显升高,表明荷瘤小鼠MDSCs的比例与肿瘤的进展密切相关；肿瘤组织中MDSCs主要分布于肿瘤组织与正常组织交界处,外周血中MDSCs的比例与血清TGF-β1水平呈明显正相关,提示荷瘤小鼠体内MDSCs可与肿瘤细胞相互作用和通过分泌TGF-β1发挥免疫抑制作用,造成肿瘤免疫逃逸,促进肿瘤细胞的生长、侵袭和转移。
Objective:To investigate the changes and distribution of myeloid-derived suppressor cells(MDSCs) in tumor tissues of tumor-bearing mice, analyze the correlation between MDSCs in peripheral blood and serum level of TGF-β1, and explore its significance and mechanisms in hepatocarcinoma immune escape.
Methods:Orthotopic transplantation tumor model of hepatocarcinoma in mice was established. On days 7,14, and 21 after tumor inoculation, the proportion of MDSCs in tumor tissues and peripheral blood were analyzed by flow cytometry; the location of MDSCs in tumor tissues was detected by immunohistochemistry; the level of serum TGF-β1 was tested by enzyme-linked immunosorbent assay; the correlation between MDSCs in peripheral blood and serum level of TGF-β1 was analyzed by Pearson correlation, and these were compared with healthy mice as controls.
Results:
1. The proportion of MDSCs in liver of healthy mice was (1.62±0.82)%, on days 7,14, and 21 after tumor inoculation, its proportion was (9.12±2.26)%、(14.40±2.87)%、(26.27±8.65)% respectively. The proportion of peripheral blood MDSCs in healthy mice was (3.54±2.15)%, on days 7,14, and 21 after tumor inoculation, its proportion was (9.45±2.64)%、(16.40±5.55)%、(25.28±11.32)% respectively. The proportion of MDSCs in tumor tissues and peripheral blood were significantly higher than those in control group(P<0.05), and accompany with tumor progression, the proportion of MDSCs increased gradually.
2. Immunohistochemistry staining with anti-Gr-1 antibody was used to examine the location of MDSCs in tumor tissues, it showed that there were a few MDSCs in liver of healthy mice, MDSCs were found mainly in the invasive front of tumor tissues in tumor-bearing mice, and the proportion of MDSCs increased gradually accompany with tumor progression.
3. The serum level of TGF-(β1 in healthy mice was (4.89±1.45) ng/ml, on days 7,14, and 21 after tumor inoculation, its proportion was (14.07±6.01) ng/ml、(23.98±3.27) ng/ml、(9.17±1.22) ng/ml respectively. The serum level of TGF-β1 in tumor-bearing mice was statistically higher than those in control group(P<0.05).
4. The correlation between MDSCs in peripheral blood and serum level of TGF-β1 was analyzed by Pearson correlation, it indicated that there was a significantly positive correlation between MDSCs in peripheral blood and serum level of TGF-β1(r=0.564, P＜0.05).
Conclusion:Accompany with tumor progression, the proportion of MDSCs in tumor tissues and peripheral blood increased gradually, suggesting a close relationship between MDSCs in tumor-bearing mice and tumor progression. MDSCs were accumulated in tumor tissues especially in the invasive front, the proportion of peripheral blood MDSCs was positively correlated with serum level of TGF-β1, these suggested that MDSCs can exert their immunosuppressive function through interaction with tumor cells and secretion of immunosuppressive TGF-β1, induce tumor immune escape, promote tumor cells growth、invasion and metastasis.
方法：建立小鼠原位肝癌模型,于荷瘤7d、14d、21d天取材,流式细胞仪检测荷瘤小鼠肿瘤组织和外周血中MDSCs的比例；免疫组织化学法检测MDSCs在肿瘤组织中的分布情况；酶联免疫吸附试验(enzyme-linked immunosorbent assay, ELISA)检测血清TGF-β1的水平；分析外周血中MDSCs比例与血清TGF-β1水平的相关性,以健康正常小鼠作对照。
结果：
1.正常小鼠肝组织中MDSCs的比例很低,为(1.62+0.82)%,荷瘤7d、14d、21d肿瘤组织中MDSCs的比例分别为(9.12±2.26)%、(14.40±2.87)%、(26.27±8.65)%。正常小鼠外周血中MDSCs的比例为(3.54±2.15)%,荷瘤7d、14d、21d外周血中MDSCs的比例分别为(9.45±2.64)%、(16.40±5.55)%、(25.28±11.32)%。与正常小鼠比较,荷瘤小鼠肿瘤组织和外周血中MDSCs的比例均明显升高(P<0.05),且随着荷瘤时间的延长,MDSCs的比例呈渐进性升高。
2.用anti-Gr-1抗体免疫组织化学法检测荷瘤小鼠肿瘤组织中MDSCs的分布情况,结果显示,正常小鼠肝组织中无或仅有极少量的MDSCs,肿瘤组织中MDSCs主要分布于肿瘤组织与正常组织交界处,且随肿瘤进展MDSCs比例升高。
3.正常小鼠血清TGF-β1水平为(4.89±1.45)ng/ml,荷瘤小鼠7d、14d、21d血清TGF-β1,水平分别为(14.07±6.01) ng/ml、(23.98±3.27) ng/ml、(9.17±1.22) ng/ml,与正常小鼠比较,荷瘤小鼠血清TGF-β1水平明显升高(P<0.05)。
4. Pearson相关分析结果表明：外周血中MDSCs比例与血清TGF-p,水平呈明显正相关(r=0.564,P<0.05)。
结论：随着肿瘤的进展,荷瘤小鼠肿瘤组织和外周血中MDSCs的比例明显升高,表明荷瘤小鼠MDSCs的比例与肿瘤的进展密切相关；肿瘤组织中MDSCs主要分布于肿瘤组织与正常组织交界处,外周血中MDSCs的比例与血清TGF-β1水平呈明显正相关,提示荷瘤小鼠体内MDSCs可与肿瘤细胞相互作用和通过分泌TGF-β1发挥免疫抑制作用,造成肿瘤免疫逃逸,促进肿瘤细胞的生长、侵袭和转移。
Objective:To investigate the changes and distribution of myeloid-derived suppressor cells(MDSCs) in tumor tissues of tumor-bearing mice, analyze the correlation between MDSCs in peripheral blood and serum level of TGF-β1, and explore its significance and mechanisms in hepatocarcinoma immune escape.
Methods:Orthotopic transplantation tumor model of hepatocarcinoma in mice was established. On days 7,14, and 21 after tumor inoculation, the proportion of MDSCs in tumor tissues and peripheral blood were analyzed by flow cytometry; the location of MDSCs in tumor tissues was detected by immunohistochemistry; the level of serum TGF-β1 was tested by enzyme-linked immunosorbent assay; the correlation between MDSCs in peripheral blood and serum level of TGF-β1 was analyzed by Pearson correlation, and these were compared with healthy mice as controls.
Results:
1. The proportion of MDSCs in liver of healthy mice was (1.62±0.82)%, on days 7,14, and 21 after tumor inoculation, its proportion was (9.12±2.26)%、(14.40±2.87)%、(26.27±8.65)% respectively. The proportion of peripheral blood MDSCs in healthy mice was (3.54±2.15)%, on days 7,14, and 21 after tumor inoculation, its proportion was (9.45±2.64)%、(16.40±5.55)%、(25.28±11.32)% respectively. The proportion of MDSCs in tumor tissues and peripheral blood were significantly higher than those in control group(P<0.05), and accompany with tumor progression, the proportion of MDSCs increased gradually.
2. Immunohistochemistry staining with anti-Gr-1 antibody was used to examine the location of MDSCs in tumor tissues, it showed that there were a few MDSCs in liver of healthy mice, MDSCs were found mainly in the invasive front of tumor tissues in tumor-bearing mice, and the proportion of MDSCs increased gradually accompany with tumor progression.
3. The serum level of TGF-(β1 in healthy mice was (4.89±1.45) ng/ml, on days 7,14, and 21 after tumor inoculation, its proportion was (14.07±6.01) ng/ml、(23.98±3.27) ng/ml、(9.17±1.22) ng/ml respectively. The serum level of TGF-β1 in tumor-bearing mice was statistically higher than those in control group(P<0.05).
4. The correlation between MDSCs in peripheral blood and serum level of TGF-β1 was analyzed by Pearson correlation, it indicated that there was a significantly positive correlation between MDSCs in peripheral blood and serum level of TGF-β1(r=0.564, P＜0.05).
Conclusion:Accompany with tumor progression, the proportion of MDSCs in tumor tissues and peripheral blood increased gradually, suggesting a close relationship between MDSCs in tumor-bearing mice and tumor progression. MDSCs were accumulated in tumor tissues especially in the invasive front, the proportion of peripheral blood MDSCs was positively correlated with serum level of TGF-β1, these suggested that MDSCs can exert their immunosuppressive function through interaction with tumor cells and secretion of immunosuppressive TGF-β1, induce tumor immune escape, promote tumor cells growth、invasion and metastasis.
引文
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