Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology; Department of Immunology, University of Tübingen, Tübingen;
Division of Dermatooncology, Department of Dermatology, University Medical Center;
Clin Cancer Res. 2014 Aug 15;20(16):4390-9. doi: 10.1158/1078-0432.CCR-14-1015. Epub 2014 Jun 17.
We initially observed that the presence of circulating NY-ESO-1- and/or Melan-A-specific T cells in patients with stage IV melanoma was significantly associated with prolonged survival. Here, we report the ways in which the phenotypes and functions of these T cells differentially affect survival in patients preselected for NY-ESO-1 and/or Melan-A reactivity.
We assayed functional antigen-reactive T cells recognizing NY-ESO-1 and/or Melan-A after in vitro stimulation using overlapping peptide pools. After restimulation, we assayed six cytokines simultaneously by intracellular cytokine staining. This allowed us to analyze the functional antigen response of both CD4(+) and CD8(+) T cells at the single-cell level.
We observed that NY-ESO-1 stimulated mainly CD4(+) T cells, whereas Melan-A more often stimulated CD8(+) T cells. NY-ESO-1 reactivity was not associated with an additional impact on survival, whether CD4(+) T cells, CD8(+) T cells, or both types of T cells were responding. In contrast, recognition of Melan-A by CD4(+) T cells was associated with reduced survival in our cohort of patients preselected for NY-ESO-1 and/or Melan-A reactivity (that is, in patients with exceptionally long survival). We further observed a negative effect on survival in patients with CD4(+) T cells producing IL4 and IL17 upon Melan-A stimulation. Their prognosis was comparable to patients without any Melan-A reactivity.
The nature and prognostic impact of specific T-cell responses is different according to targeted antigen. Independent from phenotype and functional aspects, NY-ESO-1 reactivity is associated with good prognosis. In terms of Melan-A, antigen-specific CD8(+) but not CD4(+) responses are associated with prolonged survival. Clin Cancer Res; 20(16); 4390-9. ©2014 AACR.
我们最初观察到，晚期黑色素瘤患者外周血中循环 NY-ESO-1 和/或 Melan-A 特异性 T 细胞的存在与延长生存时间显著相关。在此，我们报告了这些 T 细胞表型和功能差异对预先选择对 NY-ESO-1 和/或 Melan-A 有反应的患者生存的影响方式。
我们使用重叠肽库进行体外刺激后，检测识别 NY-ESO-1 和/或 Melan-A 的功能性抗原反应性 T 细胞。再刺激后，我们通过细胞内细胞因子染色同时检测六种细胞因子。这使我们能够在单细胞水平上分析 CD4(+)和 CD8(+)T 细胞的功能性抗原反应。
我们观察到 NY-ESO-1 主要刺激 CD4(+)T 细胞，而 Melan-A 更常刺激 CD8(+)T 细胞。NY-ESO-1 反应与 CD4(+)T 细胞、CD8(+)T 细胞或两种类型的 T 细胞的反应都没有额外的生存影响无关。相比之下，在我们选择对 NY-ESO-1 和/或 Melan-A 有反应的患者亚群中，CD4(+)T 细胞识别 Melan-A 与降低生存相关（即，在生存时间特别长的患者中）。我们进一步观察到，在 Melan-A 刺激下产生 IL4 和 IL17 的 CD4(+)T 细胞对生存有负面影响。他们的预后与没有任何 Melan-A 反应的患者相当。
根据靶向抗原的不同，特异性 T 细胞反应的性质和预后影响也不同。独立于表型和功能方面，NY-ESO-1 反应与良好的预后相关。在 Melan-A 方面，抗原特异性 CD8(+)但不是 CD4(+)反应与延长生存相关。临床癌症研究；20(16)；4390-9。©2014AACR。
