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

Background Conflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been demonstrated that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 deficient 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 or -proficient). We analyzed in-house and Genentech/Roche's data of three randomized trials of PD-(L)1 inhibition in NSCLC (ORIENT-11, N=171; OAK, N=699; POPLAR, N=192) and TCGA-NSCLC cohort. Results Tissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy lost or reversed in STK11-deficient tumors (HR for death, 95% CI: 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-proficient tumors (HR for death, 95% CI: 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-WT/deficient tumors had significantly worse ICB outcomes than STK11-MUT/proficient tumors. The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/IFN-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-deficient tumors but not in those with STK11-MUT tumors. Surprisingly, while high CD8+ T cell infiltration was significantly associated with prolonged survival with ICB in STK11-proficient tumors, it predicted an opposite trend towards worse ICB outcomes in STK11-deficient tumors across three trials. This suggested an association between STK11 deficiency and CD8+ T cell dysfunction which might not be reversed by PD-(L)1 blockade. Conclusions STK11 phenotype rather than mutation status can accurately distinguish ICB-refractory NSCLC patients and reflect immune suppression. It can help refine stratification algorithm for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.