Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma-猫眼课题宝

DOI：

10.1101/2021.03.19.21253661

发表时间：

2021-03

期刊：

SSRN Electronic Journal

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

L. Au;E. Hatipoglu;M. R. de Massy;K. Litchfield;A. Rowan;R. Thompson;Desiree Schnidrig;F. Byrne;G. Beattie;S. Horswell;N. Fotiadis;S. Hazell;D. Nicol;S. Shepherd;A. Fendler;R. Mason;J. Attig;K. Joshi;I. Uddin;P. Becker;M. W. Sunderland;A. Akarca;I. Puccio;William W. Yang;T. Lund;Kim Dhillon;M. Vasquez;E. Ghorani;Hang Xu;J. López;A. Green;U. Mahadeva;E. Borg;M. Mitchison;D. Moore;I. Proctor;M. Falzon;A. Furness;L. Pickering;J. Reading;R. Salgado;T. Marafioti;M. Jamal-Hanjani;G. Kassiotis;B. Chain;J. Larkin;C. Swanton;S. Quezada;S. Turajlic

透明细胞肾细胞癌（ccRCC）中的抗原识别和T细胞介导的细胞毒性仍不完全清楚。为了解决这一知识缺口，我们分析了从15名接受纳武利尤单抗治疗前后的初治患者中收集的115份多区域肿瘤样本，以及3名患者的尸检样本。我们进行了全外显子组测序、RNAseq、TCRseq、多重免疫荧光和流式细胞术分析，并与临床反应相关。我们观察到治疗前肿瘤内TCR克隆扩增，表明预先存在的免疫力。纳武单抗在应答者中维持治疗前扩增的成簇TCR克隆，表明T细胞的持续抗原驱动刺激。应答者中的T细胞富集扩增的TCF 7 + CD 8 + T细胞，并且在nivolumab结合后上调GZMK/B。相比之下，nivolumab促进了无应答者中新TCR克隆的积累，取代了治疗前扩增的克隆型。在该数据集中，突变特征与对纳武单抗的应答不相关，而人内源性逆转录病毒表达间接相关。我们的数据表明，纳武单抗通过结合预先存在的扩增的CD 8 + T细胞以增强细胞毒性来增强ccRCC中的临床应答。

Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma

文献摘要

相似文献