EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.
Cell
; 185(1): 169-183.e19, 2022 01 06.
Article
em En
| MEDLINE
| ID: mdl-34963055
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Proteínas Nucleares
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Interferon Tipo I
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Carcinoma Pulmonar de Células não Pequenas
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Evasão Tumoral
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Reparo de DNA por Recombinação
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Neoplasias Pulmonares
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Proteínas de Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2022
Tipo de documento:
Article