Cell, 2022-01, Vol.185 (1), p.169-183.e19
2022
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- Autor(en) / Beteiligte
- Titel
- EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion
- Ist Teil von
- Cell, 2022-01, Vol.185 (1), p.169-183.e19
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •KEAP1 mediates EMSY degradation, and EMSY is stabilized in KEAP1-mutant lung cancer•Loss of KEAP1 induces a BRCAness phenotype by stabilizing EMSY•EMSY stabilization suppresses the type I interferon response, promoting immune evasion•EMSY accumulation sensitizes lung cancer to PARP inhibitors and STING agonists CRL3KEAP1 targets EMSY for degradation to regulate genome stability and the type I interferon response, suggesting that PARP inhibitors and STING agonists hold therapeutic potential for the treatment of KEAP1-mutant lung cancers.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2021.12.005Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8751279
- Format
- –
- Schlagworte
- Animals, BRCAness, Carcinoma, Non-Small-Cell Lung - genetics, Carcinoma, Non-Small-Cell Lung - immunology, Carcinoma, Non-Small-Cell Lung - metabolism, Carcinoma, Non-Small-Cell Lung - pathology, Cell Line, Tumor, EMSY, Female, HEK293 Cells, Humans, immune evasion, Immunity, Innate - genetics, interferon, Interferon Type I - metabolism, KEAP1, Kelch-Like ECH-Associated Protein 1 - genetics, Kelch-Like ECH-Associated Protein 1 - metabolism, lung cancer, Lung Neoplasms - genetics, Lung Neoplasms - immunology, Lung Neoplasms - metabolism, Lung Neoplasms - pathology, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mutation, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, NSCLC, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, PARP inhibitors, Recombinational DNA Repair - genetics, Repressor Proteins - genetics, Repressor Proteins - metabolism, Signal Transduction - genetics, STING agonsts, Tumor Escape - genetics, Tumor Microenvironment - genetics, Tumor Microenvironment - immunology, ubiquitination, Xenograft Model Antitumor Assays