Authors' Affiliations: Department of Dermatology, University Medical Center; Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology, University of Tübingen, Tübingen; German Cancer Research Center (DKFZ); German Cancer Consortium (DKTK), Heidelberg; Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany; Department of Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Italy; and Skin Cancer Research Group, School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Australia.
Clin Cancer Res. 2014 Mar 15;20(6):1601-9. doi: 10.1158/1078-0432.CCR-13-2508. Epub 2013 Dec 9.
To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen-specific T cells in patients with melanoma with distant metastasis.
The percentage of CD14(+)CD11b(+)HLA-DR(-/low) MDSCs, CD4(+)CD25(+)FoxP3(+) Tregs, and the presence of NY-ESO-1- or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan-Meier and log-rank tests. Multivariate analyses were performed using Cox regression models.
NY-ESO-1-specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of >11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P < 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs.
Circulating CD14(+)CD11b(+)HLA-DR(-/low) MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches.
分析伴有远处转移的黑色素瘤患者中循环髓源抑制性细胞（MDSC）和调节性 T 细胞（Treg）与功能性肿瘤抗原特异性 T 细胞相比的预后相关性和相对影响。
通过流式细胞术分析 94 例患者中 CD14(+)CD11b(+)HLA-DR(-/low)MDSC、CD4(+)CD25(+)FoxP3(+)Treg 的比例，并在另外的 39 例患者中进行验证。根据 Kaplan-Meier 和对数秩检验计算单变量生存差异。使用 Cox 回归模型进行多变量分析。
NY-ESO-1 特异性 T 细胞、M 分期和 MDSC 频率与生存相关。NY-ESO-1 特异性 T 细胞缺失和 M 分期 M1c 独立增加了死亡风险。在不考虑抗原特异性 T 细胞结果的第二个 Cox 模型中，频率>11%的 MDSC 显示出独立的影响。在另外的患者队列中证实了其与生存的相关性。MDSC 频率较低患者的中位生存期为 13 个月，而其他患者为 8 个月（P<0.001，联合队列）。我们观察到 MDSC 水平较高与黑色素瘤抗原特异性 T 细胞缺失之间存在强烈相关性，暗示存在因果关系和临床相关的相互作用。未观察到 Treg 对预后的影响。
循环 CD14(+)CD11b(+)HLA-DR(-/low)MDSC 对晚期黑色素瘤患者的生存有负面影响，并与功能性抗原特异性 T 细胞的存在呈负相关。我们的研究结果为在治疗环境中研究 MDSC 耗竭策略提供了依据，特别是与疫苗接种或 T 细胞转移方法相结合。
