Abstract 7366: Loss of STK11 suppresses lipid metabolism to attenuate KRAS-induced immunogenicity in patients with non-small cell lung cancer
Authors: Principe Daniel , Pasquinelli Mary , Nguyen Ryan , Feldman Lawrence , Aissa Alexandre , Weinberg Frank D. 
Published: March 2024

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Though NSCLC is genetically heterogeneous, as many as 30% of NSCLC patients harbor gain-of-function mutations in the KRAS oncogene. Recent studies have demonstrated that KRAS mutations lead to extensive remodeling of the tumor immune microenvironment. However, though the effect of co-mutations in genes such as TP53 and STK11 are known to have prognostic relevance in KRAS-mutated patients, their mechanistic effect on tumor immunogenicity is largely unknown.

Methods: In the present single-center study, we enrolled a total of 189 NSCLC patients. Paraffin specimens from each underwent a standardized analysis including immunohistochemistry for PD-L1 expression, whole exome DNA sequencing, and whole transcriptome RNA sequencing.

Results: Patients with activating KRAS mutations demonstrated a significant increase in PD-L1 expression as well as in CD8+ T-cell infiltration, both of which were enhanced by co-occurring TP53 mutation. Interestingly, in patients with loss-of-function STK11 mutations, there was no association between KRAS mutation status and either PD-L1 expression or CD8+ T-cell infiltration. Subsequent genomic analysis demonstrated that KRAS/TP53 co-mutated tumors had a significant decrease in the expression of glycolysis-associated genes, and increase in several genes involved in lipid metabolism, notably Lipoprotein Lipase (LPL), Low Density Lipoprotein Receptor (LDLR), 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 LPL, LDLR, or LDLRAD4, gain-of-function KRAS mutations had no effect on tumor immunogenicity. However, in patients with robust expression of these genes, KRAS mutations were strongly associated with increased immunogenicity and associated with improved overall survival.

Conclusions: These data suggest that gain-of-function KRAS mutations are associated with an increase in immunogenicity, though this appears to be dependent on a corresponding increase in lipid metabolism. Our data further suggest that the loss of STK11 may function as a metabolic switch to suppress 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.

Citation Format: Daniel Principe, Mary Pasquinelli, Ryan Nguyen, Lawrence Feldman, Alexandre Aissa, Frank D. Weinberg. Loss of STK11 suppresses lipid metabolism to attenuate KRAS-induced immunogenicity in patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7366.