Abstract
Immune checkpoint inhibitors (ICI) have transformed the ULK1 reduces expression of IFNg-induced immunosuppressive treatment of melanoma. However, the majority of patients have genes. ULK1 binds IRF1 in the nuclear compartment of melanoma primary or acquired resistance to ICIs, limiting durable responses cells, controlling its binding to the programmed death-ligand and patient survival. IFNg signaling and the expression of IFNg-1 promoter region. In addition, pharmacologic inhibition of ULK1 stimulated genes correlate with either response or resistance to ICIs, in combination with anti-programmed cell death protein 1 therapy in a context-dependent manner. While IFNg-inducible immunosfurther reduces melanoma tumor growth in vivo. Our data suggest timulatory genes are required for response to ICIs, chronic IFNg that targeting ULK1 represses IFNg-dependent immunosuppressignaling induces the expression of immunosuppressive genes, sion. These findings support the combination of ULK1 drug-promoting resistance to these therapies. Here, we show that high targeted inhibition with ICIs for the treatment of patients with levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in melanoma to improve response rates and patient outcomes. patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive Implications: This study identifies ULK1, activated downstream genes, with minimal effects on the expression of immunostimulaof IFNg signaling, as a druggable target to overcome resistance tory genes. In contrast, genetic or pharmacologic inhibition of mechanisms to ICI therapy in metastatic melanoma.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 332-344 |
| Number of pages | 13 |
| Journal | Molecular Cancer Research |
| Volume | 21 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2023 |
Funding
I.C. Le Poole reports grants from NIH during the conduct of the study; and reports performing research on immunotherapy for melanoma that is otherwise unrelated to the manuscript contents, with (prior) support from NCI and a foundation grant; this work pertains to harnessing bleaching phenols to treat melanoma, and designing HSP70 variants to tolerize immune responses, and immuno-engineering to design T cell–based therapy for melanoma. M. Bosenberg reports other support from Sigma/EMD/Millipore outside the submitted work. E.T. Bartom reports grants from NCI during the conduct of the study. M. Kocherginsky reports grants from NCI during the conduct of the study; and in addition, has a patent for US9149485 issued and licensed to Corcept Therapeutics. D. Saleiro reports grants from NIH/NCI; and grants from H Foundation-Robert H. Lurie Comprehensive Cancer Center Basic Insights Award during the conduct of the study. No disclosures were reported by the other authors. We thank Dr. Antoni Ribas (Jonsson Comprehensive Cancer Center and David Geffen School of Medicine, University of California Los Angeles, Funding Source: R35 CA197633 NIH, Bethesda, MD) for his valuable feedback, support on our studies and for depositing the data for study accession: phs001919.v1.p1 on dbGaP. Proteomics services were performed by the Northwestern Proteomics Core Facility of the Robert H. Lurie Comprehensive Cancer Center (supported by P30 CA060553). Flow cytometry work was performed at the Northwestern University Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Facility. All histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory of the Robert H Lurie Comprehensive Cancer Center. Imaging work was performed at the Northwestern University Center for Advanced Microscopy core of the Robert H Lurie Comprehensive Cancer Center. This work was supported by an H Foundation-Robert H. Lurie Comprehensive Cancer Center Basic Insights Award (to C.M. Horvath and D. Saleiro), grants R50-CA221848 (to E.T. Bartom), P30-CA060553 (to M. Kocherginsky), R01-CA77816 (to L.C. Platanias), and R21-CA245447 (to D. Saleiro) by NIH-NCI and by a Conquer Cancer Young Investigator Award (to S.E. Fenton), supported by funder. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the American Society of Clinical Oncology, Conquer Cancer, or the funder.
ASJC Scopus subject areas
- General Medicine
