ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer

Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically eng...

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Published in:	Nature cancer Vol. 2; no. 5; pp. 503 - 514
Main Authors:	Deng, Jiehui, Thennavan, Aatish, Dolgalev, Igor, Chen, Ting, Li, Jie, Marzio, Antonio, Poirier, John T., Peng, David H., Bulatovic, Mirna, Mukhopadhyay, Subhadip, Silver, Heather, Papadopoulos, Eleni, Pyon, Val, Thakurdin, Cassandra, Han, Han, Li, Fei, Li, Shuai, Ding, Hailin, Hu, Hai, Pan, Yuanwang, Weerasekara, Vajira, Jiang, Baishan, Wang, Eric S., Ahearn, Ian, Philips, Mark, Papagiannakopoulos, Thales, Tsirigos, Aristotelis, Rothenberg, Eli, Gainor, Justin, Freeman, Gordon J., Rudin, Charles M., Gray, Nathanael S., Hammerman, Peter S., Pagano, Michele, Heymach, John V., Perou, Charles M., Bardeesy, Nabeel, Wong, Kwok-Kin
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 01.05.2021
Subjects:	Antigen Presentation Autophagy-Related Protein-1 Homolog - genetics Carcinoma, Non-Small-Cell Lung - drug therapy Cell cycle DNA repair Experiments Humans Intracellular Signaling Peptides and Proteins Kinases Lung cancer Lung Neoplasms - drug therapy Mutation Phosphorylation Recruitment Tumors
ISSN:	2662-1347, 2662-1347
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Summary:	Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity.Wong and colleagues show that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, and propose dual targeting of ULK1 and PD-1 for these tumors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 J.D. and K.K.W. conceived and designed the experiment. J.D. performed the majority of the experiments in this manuscript. A.T. and J.D. design and performed the pathway, gene expression and GSEA analysis, I.D. and J.D. design and performed mutational load and mutational signature analysis. J.T.P. performed NSCLC patients’ specimen TMB score analysis. J.D., H.S. and C.T. performed HR and MHEJ analysis. A.M. performed chromatin binding assay, immunoprecipitation and DSB foci analysis. M.B. and D.P. performed WB for antigen presentation pathway. M.B. and D.P. generated Ulk1 shRNA and Atg cell lines. F.L. and H.Hu. generated KL cell lines. F.L., Y.P. and H.D. generated and characterized KLP cell lines. J.D. H.D., D.P. and H.Han. performed immunoproteasome activity assay. J.D., T.C., E.P. V.P., C.T., S.L. and H.Hu. performed animal experiment, treatment study and MRI imaging and analysis. J.D. and E.P. performed immune analysis of the animal models. T.C. performed cell growth assay. J.L., J.D. and S.M. performed autophagy flux analysis. J.L. performed EM experiment and analysis. J.D., B.J. and N.S.G. participated Ulk1 inhibitor experiment. J.D. and N.B. drafted the manuscript. J.D. K.K.W., N.B., V.W., E.S.W., P.S.H., N.S.G., T.P., A.T., M.Pagano, E.R., J.G., G.J.F., C.M.R., J.V.H., C.M. P., I.A., and M.Philips. conceptually designed and edited the manuscript. K.K.W. conceived, designed and supervised all the experiments. All authors reviewed and discussed the final version of the manuscript. Author contributions
ISSN:	2662-1347 2662-1347
DOI:	10.1038/s43018-021-00208-6