美国基因泰克公司Yulei Wang研究团队揭示atezolizumab联合贝伐珠单抗治疗晚期肝细胞癌的临床反应和耐药性的分子关联。相关论文于2022年6月23日在线发表在《自然—医学》杂志上。
Author: Zhu, Andrew X., Abbas, Alexander R., de Galarreta, Marina Ruiz, Guan, Yinghui, Lu, Shan, Koeppen, Hartmut, Zhang, Wenjun, Hsu, Chih-Hung, He, Aiwu Ruth, Ryoo, Baek-Yeol, Yau, Thomas, Kaseb, Ahmed O., Burgoyne, Adam M., Dayyani, Farshid, Spahn, Jessica, Verret, Wendy, Finn, Richard S., Toh, Han Chong, Lujambio, Amaia, Wang, Yulei
Issue&Volume: 2022-06-23
Abstract: Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase1b or IMbrave150 phase3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8+Tcell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory Tcell (Treg) to effector Tcell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.
DOI: 10.1038/s41591-022-01868-2
Source: https://www.nature.com/articles/s41591-022-01868-2
Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:87.241
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex
本期文章:《自然—医学》:Online/在线发表