PO.IM01.12 · 免疫学
恢复二肽基肽酶4促进KRAS-LKB1突变型肺癌的抗肿瘤免疫
Dipeptidyl peptidase 4 restoration facilitates anti-tumor immunity in KRAS-LKB1-mutant lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
KRAS-肝激酶B1（LKB1）突变型（KL）非小细胞肺癌（NSCLC）是一种侵袭性亚型，其特征为高度免疫抑制的肿瘤微环境（TME）以及对免疫检查点抑制剂（ICI）的不良应答。尽管KL肿瘤携带高肿瘤突变负荷，但其表现为免疫细胞浸润减少、PD-L1表达低下以及干扰素和细胞毒性信号传导受抑制。为阐明这种免疫抗性的分子基础，我们进行了多组学分析，发现LKB1缺失抑制了二肽基肽酶4（DPP4）的mRNA、蛋白质和酶活性，DPP4是一种参与免疫调节的膜结合糖蛋白。在KRAS突变型肺癌细胞中恢复DPP4表达可重编程TME，并显著增加了与T细胞迁移和自然杀伤（NK）细胞激活相关的免疫相关基因特征。在三维微流控模型中，DPP4过表达增强了NK细胞的趋化性和对球状体的靶向作用。在同基因KL小鼠模型中，DPP4恢复与抗PD-1治疗协同作用，导致显著的肿瘤消退和免疫激活。这些发现首次证明LKB1主动调控DPP4，确立了DPP4作为KRAS突变型NSCLC中关键免疫调节因子的地位。LKB1缺失可能代表一种主动的免疫逃逸机制，即肿瘤细胞抑制DPP4介导的免疫激活以形成免疫冷TME。与近期将STK11和KEAP1共突变与PD-L1阴性或免疫荒漠表型相联系的观察结果一致，我们的数据支持DPP4抑制促成KL-NSCLC免疫排斥的概念。相反，DPP4恢复促进了NK细胞迁移并增强了对PD-1阻断的应答，突显了其在重编程TME中的作用。虽然DPP4在肿瘤免疫中具有情境依赖性功能，但我们的研究表明恢复而非抑制DPP4可增强免疫效应细胞的募集并促进抗肿瘤免疫。总之，这些发现突显DPP4作为关键免疫调节因子和有前景的治疗靶点，可克服ICI抗性并改善KRAS-LKB1突变型肺癌的免疫治疗结局。
查看英文原文 English abstract
KRAS-liver kinase B1 (LKB1)-mutant (KL) non-small cell lung cancer (NSCLC) represents an aggressive subtype characterized by a profoundly immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint inhibitors (ICIs). Despite harboring a high tumor mutation burden, KL tumors exhibit reduced immune cell infiltration, low PD-L1 expression, and suppressed interferon and cytotoxic signaling. To elucidate the molecular basis of this immune resistance, we performed multi-omics analyses and found that loss of LKB1 suppresses the mRNA, protein, and enzymatic activity of dipeptidyl peptidase 4 (DPP4), a membrane-bound glycoprotein involved in immune modulation. Restoration of DPP4 expression in KRAS-mutant lung cancer cells reprogrammed the TME and markedly increased immune-related gene signatures associated with T-cell migration and natural killer (NK) cell activation. In three-dimensional microfluidic models, DPP4 overexpression enhanced NK cell chemotaxis and spheroid targeting. In syngeneic KL murine models, DPP4 restoration synergized with anti-PD-1 therapy, leading to significant tumor regression and immune activation. These findings provide the first evidence that LKB1 actively regulates DPP4, establishing DPP4 as a pivotal immune modulator in KRAS-mutated NSCLC. The loss of LKB1 may represent an active mechanism of immune evasion, wherein tumor cells suppress DPP4-mediated immune activation to create an immune-cold TME. Consistent with recent observations linking STK11 and KEAP1 co-mutations to PD-L1-negative or immune desert phenotypes, our data support the concept that DPP4 suppression contributes to immune exclusion in KL-NSCLC. Conversely, DPP4 restoration promoted NK cell migration and enhanced responsiveness to PD-1 blockade, underscoring its role in reprogramming the TME. While DPP4 has context-dependent functions in cancer immunity, our study demonstrates that restoring, rather than inhibiting, DPP4 enhances immune effector recruitment and facilitates antitumor immunity. Collectively, these findings highlight DPP4 as a key immune regulator and promising therapeutic target to overcome ICI resistance and improve immunotherapy outcomes in KRAS-LKB1-mutant lung cancer.
利益披露 Disclosure
H. Yanada, None.