Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional <i>STK11</i> Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

Abstract

Mutations in the <i>STK11 (LKB1)</i> 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. <i>STK11</i> mutations were associated with resistance to the anti-PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of <i>KRAS</i> mutational status, highlighting <i>STK11</i> 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 <i>STK11</i> mutations, with increased expression of markers associated with neutrophils (i.e., <i>CXCL2</i>, <i>IL6</i>), Th17 contexture (i.e., <i>IL17A</i>), 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 <i>STK11</i> knockout models. These results suggest that <i>STK11</i> mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. SIGNIFICANCE: Patients with nonsquamous <i>STK11</i>-mutant (<i>STK11</i>mut) NSCLC are less likely than <i>STK11</i> wild-type (<i>STK11</i>wt) 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 <i>STK11</i>mut NSCLC.<i>This article is highlighted in the In This Issue feature, p. 2659</i>.