Circulating and Tumor-Infiltrating Myeloid-Derived Suppressor Cells in Patients with Colorectal Carcinoma

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. In patients with colon cancer, MDSCs have recently been described as Lin−/lowHLA-DR−CD11b+CD33+ cells correlating with cancer stage, metastasis and chemotherapy response. To learn in more detail the dynamic change and clinical relevance of circulating and tumor-infiltrating Lin−/lowHLA-DR−CD11b+CD33+ MDSC in colorectal cancer, we harvested the blood from 64 patients with varying stage of colorectal cancer and tumor and matched paraneoplastic tissues from 5 patients with advanced colorectal cancer, subjected them to multicolor flow cytometric analysis of percentage, absolute number and phenotype of MDSC and finally characterized their immunosuppressive functions. Our results demonstrate that peripheral blood from colorectal cancer patients contains markedly increased percentage and absolute number of Lin−/lowHLA-DR−CD11b+CD33+ MDSCs compared with healthy individuals, and this increase is closely correlated with clinical cancer stage and tumor metastasis but not primary tumor size and serum concentrations of cancer biomarker. A similar increase of MDSCs was also observed in the tumor tissues. Phenotyping MDSCs shows that they express high CD13 and CD39, low CD115, CD117, CD124 and PD-L1, and devoid of CD14, CD15 and CD66b, reminiscent of precursor myeloid cells. MDSCs from cancer patients but not healthy donors have the immunosuppressive activity and were able to inhibit in vitro autologous T-cell proliferation. Collectively, this study substantiates the presence of increased immunosuppressive circulating and tumor-resident Lin−/lowHLA-DR−CD11b+CD33+ MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis, and suggests that pharmacologic blockade of MDSCs should be considered in future clinical trials.

髓系来源抑制细胞（Myeloid-derived suppressor cells, MDSCs）是一类异质性髓系细胞家族，可在荷瘤宿主体内抑制T细胞免疫。在结肠癌患者中，MDSCs近来被鉴定为Lin−/lowHLA-DR−CD11b+CD33+细胞，其水平与肿瘤分期、转移及化疗应答相关。为深入解析结直肠癌患者体内循环及肿瘤浸润性Lin−/lowHLA-DR−CD11b+CD33+ MDSCs的动态变化与临床相关性，本研究采集了64例不同分期结直肠癌患者的外周血，以及5例晚期结直肠癌患者的肿瘤组织与配对癌旁组织，对样本进行多色流式细胞术分析以检测MDSCs的比例、绝对计数及表型，并最终表征其免疫抑制功能。研究结果显示，与健康个体相比，结直肠癌患者外周血中Lin−/lowHLA-DR−CD11b+CD33+ MDSCs的比例及绝对计数显著升高，且该升高与临床肿瘤分期及肿瘤转移密切相关，但与原发肿瘤大小及血清肿瘤生物标志物浓度无关。肿瘤组织中也观察到MDSCs的类似升高现象。对MDSCs的表型分析显示，其高表达CD13与CD39，低表达CD115、CD117、CD124及PD-L1，且不表达CD14、CD15与CD66b，该表型与髓系前体细胞特征相似。结直肠癌患者来源的MDSCs（而非健康供者）具备免疫抑制活性，可在体外抑制自体T细胞增殖。综上，本研究证实结直肠癌患者体内循环及肿瘤驻留的Lin−/lowHLA-DR−CD11b+CD33+ MDSCs的免疫抑制活性升高，且该现象与肿瘤分期及转移相关，提示未来临床试验可考虑采用靶向MDSCs的药物阻断策略。