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Updated: Jun 7, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
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.
Purpose:
Co-mutations of the Kirsten rat sarcoma virus (KRAS) and serine/threonine kinase 11 (STK11) genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. Although neoadjuvant chemoimmunotherapy is now a standard-of-care treatment for resectable NSCLC, the clinical and immunologic impacts of KRAS and STK11 co-mutations in this setting are unknown.
Experimental Design:
We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occurring STK11 mutations, treated with neoadjuvant ICB. Single-cell transcriptomics was performed on tumor-infiltrating T cells from seven KRASmut/STK11wt tumors and six KRAS and STK11 co-mutated (KRASmut/STK11mut) tumors.
Results:
Relative to KRASmut/STK11wt tumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased prostaglandin E2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TILs from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT).
Conclusions:
These divergent T-cell transcriptional fates suggest that T-cell maintenance and residence may be detrimental to antitumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning prostaglandin E2 signaling and IL-2 signaling as they relate to T-cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.
Insights
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.
