CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients
CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients
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DOI：
10.1172/jci.insight.97022
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发表时间：
2018-03-22
期刊：
影响因子：
8
通讯作者：
Rustgi, Anil K.
中科院分区：
文献类型：
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作者：
Karakasheva, Tatiana A.;Dominguez, George A.;Rustgi, Anil K.
背景。髓源性抑制细胞（Myeloid-derived suppressor cells, MDSCs）是一群未成熟的免疫细胞，具有多种致瘤功能。CD38是食管癌小鼠模型中由MDSCs表达的一种跨膜受体-外酶。我们假设CD38可以在人结直肠癌（CRC）的MDSCs上表达，这可能为用抗CD38单克隆抗体靶向人结直肠癌的治疗提供了新的视角。采集41例结直肠癌患者和8例健康供者的血样，进行外周血单个核细胞（PBMC）分离。流式细胞术检测多形核（PMN-）和单核细胞（M-） MDSCs和CD38的表达水平。混合淋巴细胞反应（MLR）试验证实了10例结直肠癌患者M-MDSCs的免疫抑制能力。与健康供者相比，在结直肠癌患者的pbmc中观察到CD38(+) M-MDSCs的显著扩增和CD38(+) PMN-MDSCs的扩增趋势（同时伴有m -和PMN-MDSCs上CD38表达的增加趋势）。与成熟单核细胞相比，来自结直肠癌患者的CD38(+) M-MDSCs具有免疫抑制作用。与未接受治疗的CRC患者相比，接受过治疗的CRC患者CD38(+) m -和PMN-MDSC频率明显更高。该研究为在转移性结直肠癌患者中使用抗cd38单克隆抗体靶向M-MDSCs提供了理论依据。
BACKGROUND. Myeloid-derived suppressor cells (MDSCs) are a population of immature immune cells with several protumorigenic functions. CD38 is a transmembrane receptor-ectoenzyme expressed by MDSCs in murine models of esophageal cancer. We hypothesized that CD38 could be expressed on MDSCs in human colorectal cancer (CRC), which might allow for a new perspective on therapeutic targeting of human MDSCs with anti-CD38 monoclonal antibodies in this cancer.METHODS. Blood samples were collected from 41 CRC patients and 8 healthy donors, followed by peripheral blood mononuclear cell (PBMC) separation. Polymorphonuclear (PMN-) and monocytic (M-) MDSCs and CD38 expression levels were quantified by flow cytometry. The immunosuppressive capacity of M-MDSCs from 10 CRC patients was validated in a mixed lymphocyte reaction (MLR) assay.RESULTS. A significant expansion of CD38(+) M-MDSCs and a trend of expansion of CD38(+) PMN-MDSCs (accompanied by a trend of increased CD38 expression on both M-and PMN-MDSCs) were observed in PBMCs of CRC patients when compared with healthy donors. The CD38(+) M-MDSCs from CRC patients were found to be immunosuppressive when compared with mature monocytes. CD38(+) M-and PMN-MDSC frequencies were significantly higher in CRC patients who previously received treatment when compared with treatment-naive patients.CONCLUSIONS. This study provides a rationale for an attempt to target M-MDSCs with an anti-CD38 monoclonal antibody in metastatic CRC patients.