STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC

Abstract

Introduction: Conflicting 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.

Methods: Selected functional STK11 events and LKB1 protein data were leveraged to establish a transcriptomics-based classifier of STK11 phenotype (STK11-deficient [-def] or -proficient [-prof]). We analyzed in-house and Genentech/Roche's data of three randomized trials of programmed cell death protein-1 or programmed death-ligand 1 (PD-L1) inhibition in NSCLC (ORIENT-11, n = 171; OAK, n = 699; POPLAR, n = 192) and The Cancer Genome Atlas-NSCLC cohort.

Results: Tissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy were lost or reversed in STK11-def tumors (hazard ratios for death, 95% confidence interval: OAK [0.97, 0.69-1.35]; POPLAR [1.61, 0.88-2.97]; ORIENT-11 [1.07, 0.50-2.29]), while remaining in STK11-prof tumors (hazard ratios for death, 95% confidence interval: OAK [0.81, 0.66-0.99]; POPLAR [0.66, 0.46-0.95]; ORIENT-11 [0.59, 0.37-0.92]). In tumors differentially classified by phenotype and mutation status, STK11-wild-type/def tumors had significantly worse ICB outcomes than STK11-mutated (STK11-MUT)/prof tumors (p < 0.05). The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/interferon-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-def tumors rather than those with STK11-MUT tumors. Surprisingly, whereas high CD8⁺ T-cell infiltration was significantly associated with prolonged survival with ICB in STK11-prof tumors (p < 0.05 for 3 trials), it predicted an opposite trend toward worse ICB outcomes in STK11-def tumors across three trials. This suggested an association between STK11 deficiency and CD8⁺ T-cell dysfunction, which might not be reversed by programmed cell death protein 1 or PD-L1 blockade.

Conclusions: STK11 phenotype rather than mutation status can accurately identify patients with ICB-refractory NSCLC and reflect immune suppression. It can help refine stratification algorithms for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.

Keywords: CD8(+) T-cells; IFN-I; Immune checkpoint inhibitor; LKB1; STING; STK11.