Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, Anhui, P. R. China.
School of Nursing, Anhui Medical University, Hefei, Anhui, P. R. China.
Cancer Commun (Lond). 2024 Nov;44(11):1350-1373. doi: 10.1002/cac2.12609. Epub 2024 Sep 28.
Despite significant strides in lung cancer immunotherapy, the response rates for Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven lung adenocarcinoma (LUAD) patients remain limited. Fibrinogen-like protein 1 (FGL1) is a newly identified immune checkpoint target, and the study of related resistance mechanisms is crucial for improving the treatment outcomes of LUAD patients. This study aimed to elucidate the potential mechanism by which FGL1 regulates the tumor microenvironment in KRAS-mutated cancer.
The expression levels of FGL1 and SET1 histone methyltransferase (SET1A) in lung cancer were assessed using public databases and clinical samples. Lentiviruses were constructed for transduction to overexpress or silence FGL1 in lung cancer cells and mouse models. The effects of FGL1 and Yes-associated protein (Yap) on the immunoreactivity of cytotoxic T cells in tumor tissues were evaluated using immunofluorescence staining and flow cytometry. Chromatin immunoprecipitation and dual luciferase reporter assays were used to study the SET1A-directed transcriptional program.
Upregulation of FGL1 expression in KRAS-mutated cancer was inversely correlated with the infiltration of CD8 T cells. Mechanistically, KRAS activated extracellular signal-regulated kinase 1/2 (ERK1/2), which subsequently phosphorylated SET1A and increased its stability and nuclear localization. SET1A-mediated methylation of Yap led to Yap sequestration in the nucleus, thereby promoting Yap-induced transcription of FGL1 and immune evasion in KRAS-driven LUAD. Notably, dual blockade of programmed cell death-1 (PD-1) and FGL1 further increased the therapeutic efficacy of anti-PD-1 immunotherapy in LUAD patients.
FGL1 could be used as a diagnostic biomarker of KRAS-mutated lung cancer, and targeting the Yap-FGL1 axis could increase the efficacy of anti-PD-1 immunotherapy.
尽管肺癌免疫疗法取得了重大进展，但 Kirsten 大鼠肉瘤病毒致癌基因同源物（KRAS）驱动的肺腺癌（LUAD）患者的反应率仍然有限。纤维蛋白原样蛋白 1（FGL1）是新发现的免疫检查点靶标，研究相关的耐药机制对于改善 LUAD 患者的治疗效果至关重要。本研究旨在阐明 FGL1 调节 KRAS 突变型癌症肿瘤微环境的潜在机制。
使用公共数据库和临床样本评估肺癌中 FGL1 和 SET1 组蛋白甲基转移酶（SET1A）的表达水平。构建慢病毒转导以在肺癌细胞和小鼠模型中转染过表达或沉默 FGL1。使用免疫荧光染色和流式细胞术评估 FGL1 和 Yes 相关蛋白（Yap）对肿瘤组织中细胞毒性 T 细胞免疫反应性的影响。使用染色质免疫沉淀和双荧光素酶报告基因检测来研究 SET1A 指导的转录程序。
KRAS 突变型癌症中 FGL1 表达的上调与 CD8 T 细胞的浸润呈负相关。在机制上，KRAS 激活细胞外信号调节激酶 1/2（ERK1/2），随后磷酸化 SET1A，增加其稳定性和核定位。SET1A 介导的 Yap 甲基化导致 Yap 被隔离在核内，从而促进 Yap 诱导的 FGL1 转录和 KRAS 驱动的 LUAD 中的免疫逃逸。值得注意的是，程序性细胞死亡蛋白 1（PD-1）和 FGL1 的双重阻断进一步提高了 LUAD 患者抗 PD-1 免疫治疗的疗效。
FGL1 可作为 KRAS 突变型肺癌的诊断生物标志物，靶向 Yap-FGL1 轴可提高抗 PD-1 免疫治疗的疗效。
