Title | EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Marzio 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 |
Journal | Cell |
Volume | 185 |
Issue | 1 |
Pagination | 169-183.e19 |
Date Published | 2022 01 06 |
ISSN | 1097-4172 |
Keywords | Animals, 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. |
DOI | 10.1016/j.cell.2021.12.005 |
Alternate Journal | Cell |
PubMed ID | 34963055 |
PubMed Central ID | PMC8751279 |
Grant List | F30 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 Lab:
Related Faculty:
Antonio Marzio, Ph.D.