美国马萨诸塞州总医院Justin F. Gainor，麻省理工学院(MIT)和哈佛大学Gad Getz和Nir Hacohen团队共同合作，近期取得重要工作进展。他们对晚期非小细胞肺癌（NSCLC）检查点阻断反应的基因组学和转录组学进行了研究分析。相关研究成果2023年4月6日在线发表于《自然—遗传学》杂志上。

据介绍，抗PD-1/PD-L1药物改变了晚期NSCLC的治疗前景。

为了扩大人们对NSCLC应对检查点抑制剂反应的分子特征的了解，研究人员描述了Stand Up To Cancer-Mark Foundation队列的首次联合分析，该队列来自393名接受抗PD-(L)1治疗的NSCLC患者的全外显子组和/或RNA测序资源，以及匹配的临床反应注解。研究人员鉴定出了分子特征和结果之间的许多关联，包括（1）有利（例如，ATM改变）和不利（例如，TERT扩增）的基因组亚群，（2）免疫蛋白酶体可诱导成分的表达和反应之间的显著关联，以及（3）对检查点阻断反应增强的去分化肿瘤固有亚型。

综上所述，这一结果表明，免疫治疗结果背后的生物决定因素的复杂性，并增强了在大型、精心策划的癌症特异性队列中进行综合分析的发现潜力。

附：英文原文

Title: Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer

Author: Ravi, Arvind, Hellmann, Matthew D., Arniella, Monica B., Holton, Mark, Freeman, Samuel S., Naranbhai, Vivek, Stewart, Chip, Leshchiner, Ignaty, Kim, Jaegil, Akiyama, Yo, Griffin, Aaron T., Vokes, Natalie I., Sakhi, Mustafa, Kamesan, Vashine, Rizvi, Hira, Ricciuti, Biagio, Forde, Patrick M., Anagnostou, Valsamo, Riess, Jonathan W., Gibbons, Don L., Pennell, Nathan A., Velcheti, Vamsidhar, Digumarthy, Subba R., Mino-Kenudson, Mari, Califano, Andrea, Heymach, John V., Herbst, Roy S., Brahmer, Julie R., Schalper, Kurt A., Velculescu, Victor E., Henick, Brian S., Rizvi, Naiyer, Jnne, Pasi A., Awad, Mark M., Chow, Andrew, Greenbaum, Benjamin D., Luksza, Marta, Shaw, Alice T., Wolchok, Jedd, Hacohen, Nir, Getz, Gad, Gainor, Justin F.

Issue&Volume: 2023-04-06

Abstract: Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

DOI: 10.1038/s41588-023-01355-5

Source: https://www.nature.com/articles/s41588-023-01355-5