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Updated: Jun 7, 2025
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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
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Divergent Clinical and Immunologic Outcomes Based on STK11 Co-mutation Status in Resectable KRAS-Mutant Lung Cancers
Samuel Rosner1,2, Sydney Connor1,3, Khaled Sanber1,4
1Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
Summary
KRAS and STK11 co-mutations in non-small cell lung cancer (NSCLC) increase recurrence risk after neoadjuvant chemoimmunotherapy. T-cell residence molecules may impair anti-tumor immunity in these NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Co-mutations in Kirsten rat sarcoma virus (KRAS) and serine/threonine kinase 11 (STK11) genes are linked to resistance against immune checkpoint blockade (ICB) in advanced non-small cell lung cancer (NSCLC).
- Neoadjuvant chemoimmunotherapy is a standard treatment for resectable NSCLC, but the impact of KRAS/STK11 co-mutations in this setting is not well understood.
Purpose of the Study:
- To evaluate recurrence-free survival in resectable KRAS-mutated NSCLC with or without STK11 co-mutations treated with neoadjuvant ICB.
- To investigate the immunologic differences between KRASmut/STK11wt and KRASmut/STK11mut NSCLC tumors using single-cell transcriptomics.
Main Methods:
- Comparison of recurrence-free survival in resectable NSCLC patients with KRAS mutations, stratified by STK11 co-mutation status, following neoadjuvant ICB.
- Single-cell transcriptomics analysis of tumor-infiltrating T cells from KRASmut/STK11wt and KRASmut/STK11mut NSCLC tumors.
Main Results:
- KRASmut/STK11mut NSCLC exhibited a significantly higher risk of recurrence compared to KRASmut/STK11wt tumors.
- Single-cell analysis revealed enhanced oxidative phosphorylation and altered prostaglandin E2 and IL-2 signaling in CD8+ T cells from KRASmut/STK11mut tumors.
- Tumor-infiltrating lymphocytes (TILs) in KRASmut/STK11mut tumors showed increased expression of molecules associated with T-cell residence, such as CD39 and ZNF683.
Conclusions:
- Divergent T-cell transcriptional profiles suggest that T-cell maintenance and residence might compromise anti-tumor immunity during neoadjuvant ICB for resectable NSCLC.
- Further research is warranted to elucidate the roles of prostaglandin E2 and IL-2 signaling in T-cell immunity and clinical outcomes in KRASmut/STK11mut NSCLC.
