Project description:Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for early-stage NSCLC, the clinical and immunologic impact of KRAS and STK11 co-mutations in this setting are unknown. We evaluated the clinical outcomes and intratumoral T cell profiles of resected KRAS-mutant tumors treated with neoadjuvant ICB. Relative to KRASmut/STK11wt tumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 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. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT). These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor 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 PGE-2 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.

2024-10-24 | GSE280232 | GEO

Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer.

Project description: Not available

| S-EPMC3665805 | biostudies-literature

Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer.

Project description: Not available

| S-EPMC8120188 | biostudies-literature

Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer.

Project description: Not available

| S-EPMC9745189 | biostudies-literature

Role of immunotherapy and co-mutations on KRAS-mutant non-small cell lung cancer survival.

Project description: Not available