Leveraging Transcriptomics Data to Refine Immunotherapy Response Prediction in NSCLC: STK11 Deficiency and Beyond

We read the article by Li et al., 1 Li A, Wang Y, Yu Z, et al. STK11/LKB1 deficient phenotype rather than mutation diminishes immunotherapy efficacy and represents STING/IFN-I/CD8(+) T cell dysfunction in non-small cell lung cancer [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2023.07.020. Accessed July 29, 2023. Google Scholar recently published in the Journal of Thoracic Oncology, with great interest. The authors reported that the STK11-deficient phenotype, rather than mutation, is associated with a reduced response to immune checkpoint blockade (ICB) therapy in NSCLC by evaluating the ORIENT-11, OAK, and POPLAR trials, and The Cancer Genome Atlas–NSCLC cohort. Furthermore, they revealed underlying mechanisms such as depleted STING and interferon-I activity and CD8-positive T-cell dysfunction in STK11-deficient tumors. These findings provide valuable insights into the effects of STK11 deficiency on ICB response. We speculate that considering some additional factors such as KRAS status, programmed death-ligand 1 (PD-L1) expression and immune infiltration, could provide additional insights. STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLCJournal of Thoracic OncologyVol. 18Issue 12PreviewConflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been reported that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 phenotype rather than mutation may better stratify ICB outcomes. Full-Text PDF Open AccessSTK11/LKB1 and Immune Phenotypes Co-Determine Immunotherapy OutcomesJournal of Thoracic OncologyVol. 18Issue 11PreviewWe appreciate Amori et al. for their valuable comments on our article.1 This work used three high-quality randomized controlled trials (RCTs) to present the negative impact of the STK11-deficient (STK11-def) phenotype beyond mutation on immune checkpoint blockade (ICB) efficacy in NSCLC.1 A recent proteogenomic study suggested that down-regulation of STK11 is also crucial for lung tumors lacking STK11 mutations,2 further emphasizing the necessity to evaluate the STK11 phenotype. Here, we address the question of whether STK11 phenotype, CD274 mRNA expression, and Estimation of STromal and Immune cells in MAlignant Tumours using Expression data immune score (EIS) can be integrated into a predictive biomarker panel. Full-Text PDF