EP03.03-02 Multi-omics Analysis of Immune Determinants of STK11 in Non-Small Cell Lung Cancer

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Conference Proceeding

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J Thorac Oncol


Introduction: Serine/Threonine-Protein Kinase (STK11) is one of the most common mutated genes in NSCLC. STK11 mutations have been reported to be associated with poor response to immunotherapy in NSCLC through innate resistance to anti-PD-1/PD-L1 therapy. Herein, we analyze the impact of STK11 mutations on NSCLC tumor immune microenvironment (TME) through multi-omic analyses. Methods: The Cancer Genomic Atlas (TCGA) pan cancer lung adenocarcinoma (LUAD, n=566) and squamous cell carcinoma (LUSC, n=487) cohorts were utilized in our analyses. Clinical and genomic data were retrieved through cBioportal. Immune cell infiltration through bulk tissue RNAseq was assessed through the TIMER2.0 web-based tool. The Tumor Immune Dysfunction and Exclusion (TIDE) platform was used to assess STK11 mutations correlation with cytotoxic T-lymphocytes (CTL) dysfunction. Results: In the combined LUAD and LUSC cohort, STK11 mutations were more common in LUAD patients (14%) compared to LUSC (2%). KRAS (53.8% vs 16.5%) and KEAP1 (40.5% vs 12.8%) were the two most common mutations in STK11-mutated tumors compared to STK11 wild-type. STK11 mutations were significantly associated with poor overall survival (median: 31.2 vs 53.7 months; Log-rank p=0.037) and progression-free survival (median: 21.6 vs 55.7 months; p < 0.001) compared to STK11 wild-type. In LUAD cohort, STK11 mutations were found to be significantly associated with lower CD8+ T-cells, CD4+ T-cells, M1 macrophages infiltration, and higher T-regulatory cells infiltration (p<0.05) compared to STK11 wild-type tumors. STK11 wild-type tumors with top CTL score (high CTL infiltration) had better outcomes compared to those with bottom CTL score (low CTL infiltration); whereas STK11-mutated tumors with top CTL score had worse survival compared to those with bottom CTL score (p=0.01), which indicates that STK11 mutations are associated with CTL dysfunction (Figure 1). PD-L1, PD-1, CTLA-4, and LAG3 gene expressions were higher among STK11 wild-type tumors (p<0.05). Conclusions: STK11 mutations are associated with high levels of immune-inhibitory cells, and low levels of immune-stimulatory cells and immune checkpoints expression which indicate an immune-cold TME. Moreover, STK11 mutations are associated with CTL dysfunction. These findings can explain its association with poorer outcomes and confirm its role in identifying patients who are less likely to respond to immunotherapy. [Formula presented] Keywords: STK11, Immunotherapy, Non-small Cell Lung Cancer

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