Division of Gastroenterology, Department of Medicine, Department of Genetics, and.
Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
JCI Insight. 2018 Mar 22;3(6):97022. doi: 10.1172/jci.insight.97022.
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.
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.
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.
This study provides a rationale for an attempt to target M-MDSCs with an anti-CD38 monoclonal antibody in metastatic CRC patients.
NCI P01-CA14305603, the American Cancer Society, Scott and Suzi Lustgarten Family Colon Cancer Research Fund, Hansen Foundation, and Janssen Research and Development.
髓系来源抑制细胞（MDSCs）是一群具有多种促肿瘤功能的未成熟免疫细胞。在食管癌的小鼠模型中，CD38 是一种表达于 MDSCs 的跨膜受体-胞外酶。我们假设 CD38 也可能表达于人类结直肠癌（CRC）的 MDSCs 上，这可能为在这种癌症中用抗 CD38 单克隆抗体靶向人类 MDSCs 提供新的视角。
收集 41 例 CRC 患者和 8 例健康供者的血液样本，随后分离外周血单个核细胞（PBMC）。用流式细胞术定量多形核（PMN）-MDSCs 和单核细胞（M）-MDSCs 及 CD38 的表达水平。在混合淋巴细胞反应（MLR）测定中验证了 10 例 CRC 患者的 M-MDSCs 的免疫抑制能力。
与健康供者相比，CRC 患者的 PBMC 中观察到 CD38+M-MDSC 显著扩增，且 CD38+PMN-MDSC 呈扩增趋势（同时 M-和 PMN-MDSC 上的 CD38 表达也呈上升趋势）。与成熟单核细胞相比，CRC 患者的 CD38+M-MDSC 具有免疫抑制作用。与未接受治疗的患者相比，先前接受过治疗的 CRC 患者的 CD38+M-和 PMN-MDSC 频率明显更高。
这项研究为在转移性 CRC 患者中用抗 CD38 单克隆抗体靶向 M-MDSC 提供了一个理论依据。
NCI P01-CA14305603、美国癌症协会、Scott 和 Suzi Lustgarten 家族结肠癌研究基金、Hansen 基金会和杨森研发。
