EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.

TitleEMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.
Publication TypeJournal Article
Year of Publication2022
AuthorsMarzio A, Kurz E, Sahni JM, Di Feo G, Puccini J, Jiang S, Hirsch CAlcantara, Arbini AA, Wu WL, Pass HI, Bar-Sagi D, Papagiannakopoulos T, Pagano M
JournalCell
Volume185
Issue1
Pagination169-183.e19
Date Published2022 01 06
ISSN1097-4172
KeywordsAnimals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Female, HEK293 Cells, Humans, Immunity, Innate, Interferon Type I, Kelch-Like ECH-Associated Protein 1, Lung Neoplasms, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mutation, Neoplasm Proteins, Nuclear Proteins, Recombinational DNA Repair, Repressor Proteins, Signal Transduction, Tumor Escape, Tumor Microenvironment, Xenograft Model Antitumor Assays
Abstract

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

DOI10.1016/j.cell.2021.12.005
Alternate JournalCell
PubMed ID34963055
PubMed Central IDPMC8751279
Grant ListF30 CA243205 / CA / NCI NIH HHS / United States
T32 CA009161 / CA / NCI NIH HHS / United States
P30 CA016087 / CA / NCI NIH HHS / United States
R35 CA210263 / CA / NCI NIH HHS / United States
R35 GM136250 / GM / NIGMS NIH HHS / United States
R01 CA227649 / CA / NCI NIH HHS / United States
T32 CA193111 / CA / NCI NIH HHS / United States
K00 CA212460 / CA / NCI NIH HHS / United States
F30 CA247020 / CA / NCI NIH HHS / United States
P41 EB017183 / EB / NIBIB NIH HHS / United States
R01 CA076584 / CA / NCI NIH HHS / United States
R37 CA222504 / CA / NCI NIH HHS / United States
Related Faculty: 
Antonio Marzio, Ph.D.

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