PXD035347

PXD035347 is an original dataset announced via ProteomeXchange.

Title	ULK1 as a novel therapeutic target to enhance immune checkpoint therapies against melanoma
Description	Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. Interferon-gamma (IFNg) signaling and the expression of IFNg-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNg-inducible immunostimulatory genes are required for response to ICIs, chronic IFNg signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of ULK1 correlate with poor survival in melanoma patients and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacological inhibition of ULK1 reduces expression of IFNg-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the PD-L1 promoter region. Additionally, pharmacological inhibition of ULK1 in combination with anti-PD-1 therapy further reduces melanoma tumor growth and enhances anti-tumor immune responses in vivo. Our data suggest that targeting ULK1 represses IFNg-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of melanoma patients to improve response rates and patient outcomes.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:33:36.195.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Renu Goel
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-14 07:25:13	ID requested
1	2023-02-02 15:27:57	announced
2	2023-04-11 08:30:30	announced	2023-04-11: Updated project metadata.
3	2023-04-11 08:33:26	announced	2023-04-11: Updated project metadata.
4	2023-04-12 06:24:15	announced	2023-04-12: Updated project metadata.
⏵ 5	2023-11-14 07:33:39	announced	2023-11-14: Updated project metadata.

Fenton SE, Zannikou M, Ilut L, Fischietti M, Ji C, Oku CV, Horvath CM, Le Poole IC, Bosenberg M, Bartom ET, Kocherginsky M, Platanias LC, Saleiro D, -Mediated Resistance to Immune Checkpoint Inhibitors. Mol Cancer Res, 21(4):332-344(2023) [pubmed]

submitter keyword: IRF1, interferon-gamma,ULK1, melanoma, PD-L1, signaling, immune checkpoint inhibitors

Leonidas C. Platanias
contact affiliation	Director, Robert H. Lurie Comprehensive Cancer Center Jesse, Sara, Andrew, Abigail, Benjamin and Elizabeth Lurie Professor of Oncology Professor of Medicine (Hematology and Oncology) and Biochemistry and Molecular Genetics
contact email	I-platanias@northwestern.edu
lab head
Renu Goel
contact affiliation	Northwestern University
contact email	drrenugoel@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/02/PXD035347

PRIDE project URI

• PRIDE
  1. PXD035347
     1. Label: PRIDE project
     2. Name: ULK1 as a novel therapeutic target to enhance immune checkpoint therapies against melanoma