Torok Klara, Ferencz Bence, Boettiger Kristiina, Pozonec Maria Dorothea, Pipek Orsolya, Bogos Julianna, Lantos Andras, Hegedus Zita, Schelch Karin, Radeczky Peter, Bogos Krisztina, Teglas Vivien, Megyesfalvi Evelyn, Ferenczy Anita, Renyi-Vamos Ferenc, Aigner Clemens, Megyesfalvi Zsolt, Dome Balazs, Fillinger Janos
Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
National Koranyi Institute of Pulmonology, Budapest, Hungary.
Transl Lung Cancer Res. 2025 Jun 30;14(6):1914-1928. doi: 10.21037/tlcr-2024-1092. Epub 2025 Jun 24.
Although Kirsten rat sarcoma virus (KRAS) mutations represent the most frequent oncogenic driver alterations in Caucasian lung adenocarcinoma (LADC) patients, their impact on immune phenotype and tumor morphology is largely unexplored. Here, we investigated the associations between KRAS mutation subtypes, immune landscape, and tumor heterogeneity in surgically treated LADC, with a particular focus on specific tumor growth patterns.
This study included 87 surgically treated patients with histologically confirmed early-stage LADC. Three tumorous and one non-tumorous tissue microarray (TMA) cores were collected from each patient. KRAS genotyping was performed using polymerase chain reaction (PCR)-based assays. We assessed the immune landscape by evaluating the NLRP3 inflammasome, CD3, CD163, and PD-L1 expression.
The mutational landscape concerning the type of KRAS mutation was mostly homogenous across TMA cores, with KRASG12C being the most frequently detected alteration. Notably, in 19 cases, the dominant mutational subtype differed between the tumor punctures originating from the same tumor. Although KRASG12A mutation was not detected in LADC samples with a lepidic growth pattern and micropapillary LADCs lacked wild-type KRAS gene, no statistically significant association was found between the KRAS mutation subtype and LADC growth pattern. NLRP3 expression significantly correlated with CD3 and CD163 expressions (P<0.001), and elevated NLRP3 levels were characteristic of LADCs with solid growth pattern (P=0.001). Tumor samples with solid morphology expressed significantly higher levels of PD-L1 than acinar- or lepidic-pattern LADCs (P=0.007 and P=0.002, respectively).
KRAS mutation subtypes may have a heterogeneous distribution across different tumor regions, contributing to cases with concomitant mutation subtypes that create significant diagnostic challenges. The growth pattern-specificity of NLRP3 and PD-L1 offers additional guidance for the future development of alternative immunotherapeutic approaches.
尽管 Kirsten 大鼠肉瘤病毒（KRAS）突变是白种人肺腺癌（LADC）患者中最常见的致癌驱动基因改变，但其对免疫表型和肿瘤形态的影响在很大程度上尚未得到探索。在此，我们研究了手术治疗的 LADC 中 KRAS 突变亚型、免疫微环境和肿瘤异质性之间的关联，特别关注特定的肿瘤生长模式。
本研究纳入了 87 例经手术治疗且组织学确诊为早期 LADC 的患者。从每位患者收集三个肿瘤组织和一个非肿瘤组织微阵列（TMA）核心。使用基于聚合酶链反应（PCR）的检测方法进行 KRAS 基因分型。我们通过评估 NLRP3 炎性小体、CD3、CD163 和 PD-L1 的表达来评估免疫微环境。
关于 KRAS 突变类型的突变谱在 TMA 核心之间大多是同质的，KRASG12C 是最常检测到的改变。值得注意的是，在 19 例病例中，来自同一肿瘤的肿瘤穿刺样本之间的主要突变亚型不同。尽管在具有鳞屑样生长模式的 LADC 样本中未检测到 KRASG12A 突变，且微乳头型 LADC 缺乏野生型 KRAS 基因，但在 KRAS 突变亚型与 LADC 生长模式之间未发现统计学上的显著关联。NLRP3 表达与 CD3 和 CD163 表达显著相关（P<0.001），且 NLRP3 水平升高是具有实体生长模式的 LADC 的特征（P=0.001）。具有实体形态的肿瘤样本中 PD-L1 的表达水平显著高于腺泡型或鳞屑样型 LADC（分别为 P=0.007 和 P=0.002）。
KRAS 突变亚型在不同肿瘤区域可能具有异质性分布，导致出现伴有不同突变亚型的病例，给诊断带来重大挑战。NLRP3 和 PD-L1 的生长模式特异性为未来替代免疫治疗方法的开发提供了额外的指导。
