简介：TCR曲目在免疫反应的编排中起着关键作用。特别是已经提出减少治疗前香农多样性，增加克隆性和TCR收敛性以反映肿瘤微环境中抗原特异性T细胞的克隆扩增，以上这些被认为与更好的反应率、改善的无进展生存期(PFS)和总生存期(OS)相关。我们旨在探讨NSCLC患者(PDL1)外周血中的上述TCR库特征≥50%)在一线治疗中用单药pembrolizumab治疗;并将它们与总体响应率(ORR)，改善的无进展生存期(PFS)和总生存期(OS)相关联。Introduction:TCR repertoire plays a key role on the orchestration of the immune response. In particular, reduced pre-treatment Shannon diversity, increase clonality and increase convergence of TCRs have been suggested to reflect clonal expansion of antigen-specific T-cells in the tumour microenvironment. These are thought to be correlated with better response rate, improved progression free survival (PFS) and overall survival (OS). Here we aim to explore the above TCR repertoire features in peripheral blood of NSCLC patients (with PDL1≥50%) treated with single agent pembrolizumab in the first line setting; and correlate them with overall response rate (ORR), PFS and OS.

        方法：我们前瞻性收集了48例接受一线pembrolizumab治疗的非小欧细胞性肺癌患者的基线血液。从白细胞中提取高质量的DNA，并使用Oncomine TCR Beta SR分析(Thermo Fisher)进行TCR测序。计算每个个体的TCR克隆性和收敛性，并使用Kaplan-Meier曲线和生存统计与生存相关。进行多变量分析以控制可能影响TCR库和结果(例如年龄，性别，ECOG，吸烟状况和治疗前中性粒细胞与淋巴细胞比率(NLR))关联的其他变量。

        Methods:We prospectively collected baseline blood from 48 NSCLC patients treated with first line pembrolizumab. High quality DNA was extracted from white blood cells and used for TCR sequencing using the Oncomine TCR Beta-SR Assay (Thermo Fisher). TCR clonality and convergence were calculated for each individual and correlated with survival using Kaplan-Meier curves and survival statistics. Multivariate analysis was carried out controlling for other variable that may influence the association of TCR repertoire and outcomes such as age, sex, ECOG, smoking status and pre-treatment neutrophil to lymphocyte ratio (NLR).

        结果：:我们的数据仅对29例患者进行了至少6个月的随访。我们观察到pembrolizumab有客观反应的患者治疗前TCR克隆性增加的趋势，而Shannon多样性显著降低(P = 0.042)，收敛似乎并没有影响我们队列中的ORR。此外，治疗前克隆数量减少(HR=0.54,95%CI 0.21-1.43，P=0.037)，香农多样性降低(HR=0.52,95%CI 0.20-1.38，P=0.047)，均匀度降低(HR=0.41,95%CI 0.14-1.19，P=0.044)和ELVA克隆性(HR=2.45,95%CI 0.84-7.11，P=0.044)。减少而不是增加收敛与改善PFS的趋势相关。这些参数都没有与OS相关的静态显着性。

        Results:Our data matured for 29 patients only with a follow-up of at least 6 months. We observed a trend towards increased pre-treatment TCR clonality in patients with objective response to pembrolizumab and statistically significant reduced Shannon diversity (P = 0.042). Convergence did not seem to affect ORR in our cohort. Moreover, there was a significantly longer PFS in patients with reduced number of pre-treatment clones (HR = 0.54, 95%CI 0.21-1.43, P = 0.037), reduced Shannon diversity (HR = 0.52, 95%CI 0.20-1.38, P = 0.047), reduced Evenness (HR = 0.41, 95%CI 0.14-1.19, P = 0.044) and eleva clonality(HR = 2.45, 95%CI 0.84-7.11, P = 0.044). Reduced rather than increased convergence was correlated with a trend towards improved PFS. None of these parameters were statically significant in relation to OS.

        结论：治疗前TCR克隆性增加和多样性降低与ORR和PFS改善相关，但与pembrolizumab单药治疗高PD-L1的NSCLC患者无关。该队列的进一步成熟将证明循环治疗前TCR库是否是免疫检测点抑制的预后因素。

        Conclusion:Increased pre-treatment TCR clonality and reduced diversity are associated with improved ORR and PFS, but not OS in NSCLC patients with high PD-L1 treated with pembrolizumab monotherapy. Further maturation of this cohort will demonstrate whether the circulating pre-treatment TCR repertoire is a prognostic factor for immunecheckpoint inhibition.