Department of Medicine, University of Wisconsin, Madison, Wisconsin.
Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois.
Cancer Res Commun. 2024 Aug 1;4(8):2282-2294. doi: 10.1158/2767-9764.CRC-24-0153.
As many as 30% of the patients with non-small cell lung cancer harbor oncogenic KRAS mutations, which leads to extensive remodeling of the tumor immune microenvironment. Although co-mutations in several genes have prognostic relevance in KRAS-mutated patients, their effect on tumor immunogenicity are poorly understood. In the present study, a total of 189 patients with non-small cell lung cancer underwent a standardized analysis including IHC, whole-exome DNA sequencing, and whole-transcriptome RNA sequencing. Patients with activating KRAS mutations demonstrated a significant increase in PDL1 expression and CD8+ T-cell infiltration. Both were increased in the presence of a co-occurring TP53 mutation and lost with STK11 co-mutation. Subsequent genomic analysis demonstrated that KRAS/TP53 co-mutated tumors had a significant decrease in the expression of glycolysis-associated genes and an increase in several genes involved in lipid metabolism, notably lipoprotein lipase, low-density lipoprotein receptor, and LDLRAD4. Conversely, in the immune-excluded KRAS/STK11 co-mutated group, we observed diminished lipid metabolism and no change in anaerobic glycolysis. Interestingly, in patients with low expression of lipoprotein lipase, low-density lipoprotein receptor, or LDLRAD4, KRAS mutations had no effect on tumor immunogenicity. However, in patients with robust expression of these genes, KRAS mutations were associated with increased immunogenicity and associated with improved overall survival. Our data further suggest that the loss of STK11 may function as a metabolic switch, suppressing lipid metabolism in favor of glycolysis, thereby negating KRAS-induced immunogenicity. Hence, this concept warrants continued exploration, both as a predictive biomarker and potential target for therapy in patients receiving ICI-based immunotherapy.
In patients with lung cancer, we demonstrate that KRAS mutations increase tumor immunogenicity; however, KRAS/STK11 co-mutated patients display an immune-excluded phenotype. KRAS/STK11 co-mutated patients also demonstrated significant downregulation of several key lipid metabolism genes, many of which were associated with increased immunogenicity and improved overall survival in KRAS-mutated patients. Hence, alteration to lipid metabolism warrants further study as a potential biomarker and target for therapy in patients with KRAS-mutated lung cancer.
非小细胞肺癌患者中有多达 30%携带致癌 KRAS 突变，这导致肿瘤免疫微环境发生广泛重塑。尽管 KRAS 突变患者的几种基因共突变具有预后相关性，但它们对肿瘤免疫原性的影响尚不清楚。在本研究中，总共对 189 名非小细胞肺癌患者进行了标准化分析，包括免疫组化、全外显子 DNA 测序和全转录组 RNA 测序。具有激活 KRAS 突变的患者表现出 PD-L1 表达和 CD8+T 细胞浸润的显著增加。这两者在存在共发生的 TP53 突变时增加，并且随着 STK11 共突变而丧失。随后的基因组分析表明，KRAS/TP53 共突变肿瘤中与糖酵解相关的基因表达显著降低，并且参与脂质代谢的几个基因表达增加，特别是脂蛋白脂肪酶、低密度脂蛋白受体和 LDLRAD4。相反，在免疫排斥的 KRAS/STK11 共突变组中，我们观察到脂质代谢减少，无氧糖酵解无变化。有趣的是，在脂蛋白脂肪酶、低密度脂蛋白受体或 LDLRAD4 低表达的患者中，KRAS 突变对肿瘤免疫原性没有影响。然而，在这些基因表达丰富的患者中，KRAS 突变与增强的免疫原性相关，并与改善的总生存期相关。我们的数据进一步表明，STK11 的缺失可能作为一种代谢开关起作用，抑制脂质代谢有利于糖酵解，从而否定 KRAS 诱导的免疫原性。因此，这一概念值得进一步探索，既作为接受基于 ICI 的免疫治疗的患者的预测生物标志物，也作为潜在的治疗靶点。
在肺癌患者中，我们证明 KRAS 突变增加了肿瘤的免疫原性；然而，KRAS/STK11 共突变患者表现出免疫排斥表型。KRAS/STK11 共突变患者还表现出几个关键脂质代谢基因的显著下调，其中许多基因与 KRAS 突变患者的免疫原性增加和总生存期改善相关。因此，脂质代谢的改变值得进一步研究，作为 KRAS 突变型肺癌患者的潜在生物标志物和治疗靶点。
