CPI efficacy in EMT6 STK11wt, KO, and KO/KI tumors. (A) Western blotting of STK11, phosphorylated AMPK (p-AMPK), total AMPK, and actin in lysates from wild-type EMT6 cells (EMT6 WT), STK11 CRISPR KO clone (EMT6 KO) and from STK11 KO clone engineered to re-express STK11 (EMT6 STK11 KO/KI). The ratio of phosphorylated AMPK to total AMPK (p-AMPK/total AMPK) is shown at bottom. (B) Percentage of Ly6G+ granulocytic cells among CD45+ immune cells from EMT6 WT and EMT6 STK11 KO tumors determined by flow cytometry. Survival of mice engrafted with (C) EMT6 WT, (D) EMT6 STK11 KO clone or (E) EMT6 STK11 KO clone engineered to re-express STK11 (EMT6 STK11 KO/KI) and treated with combined CPI therapy. Survival of mice engrafted with (F) EMT6 WT or (G) EMT6 STK11 KO clone 26C43 and treated with STAT3 ASO, CPI immunotherapy, or STAT3 ASO plus CPI combinations as indicated.
ARTICLE ABSTRACT
Mutations in the STK11 (LKB1) gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non–small cell lung cancer (NSCLC) enrolled in three phase I/II trials. STK11 mutations were associated with resistance to the anti–PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of KRAS mutational status, highlighting STK11 as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood, and serum revealed a unique immune phenotype in patients with STK11 mutations, with increased expression of markers associated with neutrophils (i.e., CXCL2, IL6), Th17 contexture (i.e., IL17A), and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout models. These results suggest that STK11 mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy.
Patients with nonsquamous STK11-mutant (STK11mut) NSCLC are less likely than STK11 wild-type (STK11wt) patients to respond to anti–PD-L1 ± anti-CTLA4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in STK11mut NSCLC.This article is highlighted in the In This Issue feature, p. 2659
