Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma.

Abstract

Mutations in <i>STK11</i> (<i>LKB1</i>) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TIME) and resistance to immunotherapy. The mechanisms underpinning the establishment and maintenance of a cold TIME in <i>LKB1</i>-mutant LUAD remain poorly understood. In this study, we investigated the role of the LKB1 substrate AMPK in immune evasion in human non-small cell lung cancer (NSCLC) and mouse models and explored the mechanisms involved. We addressed the role of AMPK in immune evasion in NSCLC by correlating AMPK phosphorylation and immune-suppressive signatures and by deleting <i>AMPKα1</i> (<i>Prkaa1</i>) and <i>AMPKα2</i> (<i>Prkaa2</i>) in a <i>Kras^G12D</i> -driven LUAD. Furthermore, we dissected the molecular mechanisms involved in immune evasion by comparing gene-expression signatures, AMPK activity, and immune infiltration in mouse and human LUAD and gain or loss-of-function experiments with LKB1- or AMPK-deficient cell lines. Inactivation of both AMPK<i>α</i>1 and AMPK<i>α</i>2 together with Kras activation accelerated tumorigenesis and led to tumors with reduced infiltration of CD8⁺/CD4⁺ T cells and gene signatures associated with a suppressive TIME. These signatures recapitulate those in <i>Lkb1</i>-deleted murine LUAD and in <i>LKB1-</i>deficient human NSCLC. Interestingly, a similar signature is noted in human NSCLC with low AMPK activity. In mechanistic studies, we find that compromised LKB1 and AMPK activity leads to attenuated antigen presentation in both LUAD mouse models and human NSCLC. The results provide evidence that the immune evasion noted in <i>LKB1</i>-inactivated lung cancer is due to subsequent inactivation of AMPK and attenuation of antigen presentation.