PXD066359

PXD066359 is an original dataset announced via ProteomeXchange.

Title	ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer
Description	Small cell lung cancer (SCLC) represents ~15% of all lung cancers and is characterized by its highly aggressive phenotype and its dismal outcome. Though the addition of immune checkpoint blockade to carboplatin and etoposide treatment has improved outcome in SCLC patients, SCLC cells finally acquire the ability to evade immunosurveillance and resistance against immune checkpoint blockade. To elaborate molecular mechanisms that mediate SCLC immune evasion, we performed high dimensional profiling of human and murine SCLC specimens. We herein comprehensively analyzed matched human samples of primary and metastatic SCLC and found a loss of MHC-I in SCLC metastases indicating that MHC-I loss mediates SCLC immune evasion. Silencing MHC-I in SCLC cells drastically diminished immune cell infiltration and facilitated the formation of metastasis in mice by circumventing immune surveillance. Using mass spectrometry and phospho-tyrosine kinase analysis, we discovered that ERBB2 signaling suppresses MHC-I expression in SCLC cells and stimulates immune modulating transcripts. Mechanistically, genetic and/or pharmacologic blockade of the ERBB2 signaling axis was sufficient to induce MHC-I expression and to prevent immune evasion in autochthonous murine SCLC in a STING-dependent manner. Finally, we demonstrate that the ERBB2 signaling axis regulates MHC-I expression on SCLC cells and is critical in maintaining immune evasion in SCLC. Most strikingly, we here uncover synergistic treatment efficacy by combining ERBB2 inhibition with PD-1 blockade eliciting profound responses in preclinical SCLC models and circumventing MHC-I loss under immunotherapy, suggesting this combination for future clinical trials in patients with SCLC.
HostingRepository	MassIVE
AnnounceDate	2025-10-13
AnnouncementXML	Submission_2025-10-13_02:30:48.888.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bj�rn H�upl
SpeciesList	scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090;
ModificationList	O-phospho-L-serine; O-phospho-L-threonine; O4'-phospho-L-tyrosine
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-21 04:23:19	ID requested
⏵ 1	2025-10-13 02:30:49	announced

no publication

submitter keyword: ERBB2, DatasetType:Proteomics

Roland Ullrich
contact affiliation	University cologne
contact email	roland.ullrich@uk-koeln.de
lab head
Bj�rn H�upl
contact affiliation	DKFZ/DKTK
contact email	b.haeupl@dkfz-heidelberg.de
dataset submitter

MassIVE dataset URI

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