Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany.
Lung Cancer. 2018 May;119:48-55. doi: 10.1016/j.lungcan.2018.03.002. Epub 2018 Mar 6.
This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies.
We performed T-cell receptor (TCR) β-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial.
Untreated stage IV LCNEC patients had significant T-cell repertoire alterations (p < 0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (r = 0.49, p < 0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNEC patients showed mild lymphopenia (1.54 vs. 2.51/nl in median, p < 0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157 days in median, p = 0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316 days, p = 0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.
本研究旨在评估 T 细胞在大细胞神经内分泌肺癌（LCNEC）病理生理学和治疗敏感性中的潜在重要作用，这是一种预后较差且缺乏指导新治疗策略数据的孤儿病。
我们使用年龄匹配的当前或既往（n=11）和从不吸烟者（n=10）作为对照，对接受 CRAD001KDE37 试验治疗的患者（n=35）的血液样本进行 T 细胞受体（TCR）β链谱分析。同时分析了与患者全血细胞计数以及临床试验中治疗反应和总生存数据的相关性。
与年龄匹配的吸烟者相比，未经治疗的 IV 期 LCNEC 患者存在明显的 T 细胞受体库改变（p<0.001）。这些变化与血淋巴细胞计数呈正相关（r=0.49，p<0.01），表明抗原诱导的 T 细胞增殖是致病机制。与此同时，LCNEC 患者表现出轻度淋巴细胞减少症（中位数 1.54 与 2.51/nl，p<0.01），这揭示了系统免疫失调的第二个、抗原非依赖性机制。诊断时更明显的 T 细胞受体库改变和更高的血淋巴细胞计数与 RECIST 更好的治疗反应和更长的总生存时间相关（中位数分别为 441 与 157 天，p=0.019）。治疗 3 个月后 T 细胞受体库的更高程度正常化也能区分出具有更有利预后的患者群体（中位数总生存时间分别为 617 与 316 天，p=0.036），独立于放射学反应。因此，LCNEC 会引起 T 细胞受体库的临床相关改变，这些改变可在血液中测量，并可用于预后、预测和治疗目的。其发病机制似乎涉及抗原诱导的寡克隆 T 细胞扩增，叠加 TCR 非依赖性淋巴细胞减少症。
