Inactivation of AMPK leads to attenuation of antigen presentation and immune evasion in lung adenocarcinoma Journal Article
| Authors: | Gao, Y.; Päivinen, P.; Tripathi, S.; Domènech-Moreno, E.; Wong, I. P. L.; Vaahtomeri, K.; Nagaraj, A. S.; Talwelkar, S. S.; Foretz, M.; Verschuren, E. W.; Viollet, B.; Yan, Y.; Mäkelä, T. P. |
| Article Title: | Inactivation of AMPK leads to attenuation of antigen presentation and immune evasion in lung adenocarcinoma |
| Abstract: | Purpose: Mutations in STK11 (LKB1) 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 LKB1-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. Experimental Design: We addressed the role of AMPK in immune evasion in NSCLC by correlating AMPK phosphorylation and immune-suppressive signatures and by deleting AMPKa1 (Prkaa1) and AMPKa2 (Prkaa2) in a KrasG12D-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. Results: Inactivation of both AMPKa1 and AMPKa2 together with Kras activation accelerated tumorigenesis and led to tumors with reduced infiltration of CD8þ/CD4þ T cells and gene signatures associated with a suppressive TIME. These signatures recapitulate those in Lkb1-deleted murine LUAD and in LKB1-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. Conclusions: The results provide evidence that the immune evasion noted in LKB1-inactivated lung cancer is due to subsequent inactivation of AMPK and attenuation of antigen presentation. © 2021 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-01-01 |
| Start Page: | 227 |
| End Page: | 237 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-2049 |
| PUBMED: | 34667030 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
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