ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer Journal Article
| Authors: | Deng, J.; Thennavan, A.; Dolgalev, I.; Chen, T.; Li, J.; Marzio, A.; Poirier, J. T.; Peng, D. H.; Bulatovic, M.; Mukhopadhyay, S.; Silver, H.; Papadopoulos, E.; Pyon, V.; Thakurdin, C.; Han, H.; Li, F.; Li, S.; Ding, H.; Hu, H.; Pan, Y.; Weerasekara, V.; Jiang, B.; Wang, E. S.; Ahearn, I.; Philips, M.; Papagiannakopoulos, T.; Tsirigos, A.; Rothenberg, E.; Gainor, J.; Freeman, G. J.; Rudin, C. M.; Gray, N. S.; Hammerman, P. S.; Pagano, M.; Heymach, J. V.; Perou, C. M.; Bardeesy, N.; Wong, K. K. |
| Article Title: | ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer |
| Abstract: | 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. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | gene mutation; human cell; nonhuman; flow cytometry; dna repair; gene overexpression; tumor volume; lung cancer; cytotoxicity; granzyme b; t lymphocyte receptor; antigen presentation; algorithm; antigen recognition; western blotting; cell isolation; immunoprecipitation; lentivirus vector; immunoblotting; tumor immunity; down regulation; real time polymerase chain reaction; immunosuppressive treatment; fluorescence activated cell sorting; genomic dna; complementary dna; immunofluorescence microscopy; chloroquine; growth inhibition; glutaraldehyde; protein kinase lkb1; autolysosome; bafilomycin a1; puromycin; proteinase inhibition; paraformaldehyde; immune checkpoint inhibitor; exome; gene knockdown; human; article; rna sequencing; cell growth assay; genetically engineered mouse strain; stk11 gene; whole exome sequencing; hek293t cell line; serine threonine protein kinase ulk1; receptor type tyrosine protein phosphatase c; autophagy (cellular); ferrocyanide; illumina sequencing |
| Journal Title: | Nature Cancer |
| Volume: | 2 |
| Issue: | 5 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2021-05-01 |
| Start Page: | 503 |
| End Page: | 514 |
| Language: | English |
| DOI: | 10.1038/s43018-021-00208-6 |
| PROVIDER: | scopus |
| PMCID: | PMC8205437 |
| PUBMED: | 34142094 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2021 -- Source: Scopus |
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