Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, 1873 Rama IV road, Pathumwan, Bangkok, 10330, Thailand.
Department of Pathology, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, 1873 Rama IV road, Pathumwan, Bangkok, 10330, Thailand.
Clin Transl Oncol. 2020 Jul;22(7):1117-1125. doi: 10.1007/s12094-019-02238-0. Epub 2019 Nov 21.
Non-tumor-derived circulating DNA (nt-cirDNA) of advanced non-small cell lung cancer (NSCLC), with unclear origination, is associated with prognosis. We hypothesized that a part of nt-cirDNA release from CD3 or CD8 tumor-infiltrating lymphocytes (TILs) could have clinical implications.
To investigate the feasibility of T-cell-derived circulating DNA (T-cirDNA) detection, real-time PCR with Taqman assay-specific rearranged TCRβ CDR3 region was conducted in plasma of 103 advanced NSCLC. CD3 and CD8-specific immunohistochemistry from biopsy specimen, was reviewed by one blinded pathologist to the T-cirDNA results. Prognostic impact including demographic characteristics was integrated into the model.
Circulating DNA was detectable in 100 patients with median of 4 ng ml, while median of plasma T-cirDNA was 1.71 pg ml. Median %ratio of T-cirDNA/cirDNA was 0.02%. T-cirDNA was categorized by %ratio of T-cirDNA/cirDNA as undetectable, low (≤ 1%) and high (> 1%). Paradoxical prognostic impact of T-cirDNA/cirDNA was observed. Undetectable and high T-cirDNA/cirDNA translated to independent favorable prognostic outcome, HR of 0.54 [95% CI 0.30-0.96] and 0.41 [95% CI 0.21-0.80], respectively. 43 patients were assessed for CD3/CD8 TILs and PD-L1. High intratumoral CD3/CD8 TILs but not stromal CD3 TILs was correlated with high T-cirDNA/cirDNA representing active T-lymphocyte activity to eliminate cancer cells. While the prognosis of undetectable T-cirDNA/cirDNA, represents inactivated naïve T-cell, was determined by the presence of EGFR mutation and had long durable response of EGFR inhibitors.
T-cirDNA could be a novel biomarker representing adaptive immune resistance in NSCLC patients. Further exploration as a predictive biomarker for EGFR inhibitors in setting of EGFR mutation might be warranted.
高级非小细胞肺癌（NSCLC）中非肿瘤源性循环 DNA（nt-cirDNA）起源不明，与预后相关。我们假设部分 nt-cirDNA 可能来自 CD3 或 CD8 肿瘤浸润淋巴细胞（TIL）的释放，这具有临床意义。
为了研究 T 细胞衍生循环 DNA（T-cirDNA）检测的可行性，采用 Taqman 检测对 103 例晚期 NSCLC 患者的血浆进行了实时 PCR。由一位对 T-cirDNA 结果不知情的病理学家对活检标本的 CD3 和 CD8 特异性免疫组化进行了回顾性分析。将预后影响因素（包括人口统计学特征）纳入模型。
100 例患者的循环 DNA 可检测，中位数为 4ng/ml，而血浆 T-cirDNA 的中位数为 1.71pg/ml。T-cirDNA/cirDNA 的中位数%比值为 0.02%。T-cirDNA 根据 T-cirDNA/cirDNA 的%比值分为不可检测、低（≤1%）和高（>1%）。T-cirDNA/cirDNA 呈现出矛盾的预后影响。不可检测和高 T-cirDNA/cirDNA 预示着独立的有利预后，风险比（HR）分别为 0.54（95%可信区间 0.30-0.96）和 0.41（95%可信区间 0.21-0.80）。对 43 例患者进行了 CD3/CD8 TILs 和 PD-L1 的评估。高肿瘤内 CD3/CD8 TILs（而非基质 CD3 TILs）与高 T-cirDNA/cirDNA 相关，代表了消除癌细胞的活跃 T 淋巴细胞活性。而不可检测的 T-cirDNA/cirDNA 则代表了失活的幼稚 T 细胞，其预后取决于 EGFR 突变的存在，并对 EGFR 抑制剂有长期持久的反应。
T-cirDNA 可能是一种新的 NSCLC 患者适应性免疫抵抗的生物标志物。进一步探索作为 EGFR 突变患者 EGFR 抑制剂的预测生物标志物可能是合理的。
