美国加州大学Antoni Ribas、Katie M. Campbell团队近日取得一项新成果。经过不懈努力，他们的研究发现既往抗CTLA-4治疗会影响晚期黑色素瘤中与抗PD-1反应相关的分子特征。相关论文发表在2023年4月10日出版的《癌细胞》杂志上。

研究人员分析了使用免疫检查点抑制剂（ICI）药物治疗的晚期黑色素瘤（N = 514）患者的七个样本分子数据集，以研究皮肤黑色素瘤中抗PD-1反应的临床、基因组和转录组学特征。研究发现，既往抗CTLA-4治疗与抗PD-1应答者的基因组、个体基因和基因特征差异有关。与抗CTLA-4未激活肿瘤或使用抗CTLA-4的抗PD-1无反应黑色素瘤肿瘤相比，对PD-1阻断有反应的抗CTLA-4黑色素瘤肿表现出增加的肿瘤突变负荷、炎症特征和细胞周期过程改变。

该研究揭示了一个统一的聚合资源，并发现先前CTLA-4阻断治疗与肿瘤微环境的显著差异有关，这些差异会影响PD-1阻断治疗反应的预测特征。

据悉，免疫检查点抑制剂，包括CTLA-4和PD-1阻断抗体，可对肿瘤免疫细胞浸润产生深远影响，而迄今为止报道的肿瘤浸润活检标准并不统一。

附：英文原文

Title: Prior anti-CTLA-4 therapy impacts molecular characteristics associated with anti-PD-1 response in advanced melanoma

Author: Katie M. Campbell, Meelad Amouzgar, Shannon M. Pfeiffer, Timothy R. Howes, Egmidio Medina, Michael Travers, Gabriela Steiner, Jeffrey S. Weber, Jedd D. Wolchok, James Larkin, F. Stephen Hodi, Silvia Boffo, Lisa Salvador, Daniel Tenney, Tracy Tang, Marshall A. Thompson, Christine N. Spencer, Daniel K. Wells, Antoni Ribas

Issue&Volume: 2023/04/10

Abstract: Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.

DOI: 10.1016/j.ccell.2023.03.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00083-1