Myeloid Derived Suppressor Cells: Key Drivers of Immunosuppression in Ovarian Cancer
Myeloid Derived Suppressor Cells: Key Drivers of Immunosuppression in Ovarian Cancer
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DOI：
10.3389/fimmu.2019.01273
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发表时间：
2019-06-04
影响因子：
7.3
通讯作者：
Coosemans, An
中科院分区：
文献类型：
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作者：
Baert, Thais;Vankerckhoven, Ann;Coosemans, An
肿瘤浸润淋巴细胞（TIL）的存在与晚期上皮性卵巢癌的较长总生存期相关。尽管TIL对预后有影响，但卵巢癌对检查点抑制剂和抗原特异性主动免疫治疗的反应有限。我们研究的目的是在ID8-fLuc同基因卵巢癌小鼠模型中研究卵巢癌与先天性和适应性免疫系统之间的相互作用。对于体内实验C57BU6、B6. 129S7-Rag（tm1Mom）/J和B6.129P2（SJO-Myd88（tm1.1Defr）/J小鼠接种ID8-fLuc。使用氯膦酸盐脂质体（CL）、抗CD8a、抗GR 1、抗集落刺激因子1（抗CSF 1）和TM β 1（抗CD122）进行体内耗竭实验。通过效应T细胞、调节性T细胞、自然杀伤细胞、B细胞、巨噬细胞和髓源性抑制细胞（MDSC）的荧光激活细胞分选分析、MDSC和肿瘤相关巨噬细胞（TAM）的免疫组织化学以及血管背景下M1和M2 TAM的免疫荧光进行免疫读数。体外观察MDSC对T细胞增殖和表型的影响。我们发现，与具有免疫活性的C57 BU6小鼠相比，T和B细胞的缺乏不影响B6.129 S7-Rag1（tm1 Mom）/J小鼠的肿瘤生长或存活。CL诱导的巨噬细胞消耗促进了C57 BU6小鼠（p = 0.004）和B6.129 S7-Rag1（tm1M）（om）/J小鼠（p = 0.0005）中的肿瘤增殖并缩短了生存期。在CL治疗期间，我们观察到促炎细胞因子明显增加（p
The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BU6, B6. 129S7-Rag(tm1Mom)/J, and B6.129P2(SJO-Myd88(tm1.1Defr)/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TM beta 1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1(tm1Mom)/J mice compared to immunocompetent C57BU6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BU6 mice (p = 0.004) and in B6.129S7-Rag1(tm1M)(om)/J mice = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p