PXD056501

PXD056501 is an original dataset announced via ProteomeXchange.

Title	Tumor-expressed SPPL3 supports innate anti-tumor immune responses
Description	The development of an effective anti-tumor response relies on the synergistic actions of various immune cells that recognize tumor cells via distinct receptors. Tumors, however, often manipulate receptor-ligand interactions to evade recognition by the immune system. Recently, we highlighted the role of neolacto-series glycosphingolipids (nsGSLs), produced by the enzyme β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), in tumor immune escape. We previously demonstrated that loss of signal peptide peptidase like 3 (SPPL3), an inhibitor of B3GNT5, results in elevated levels of nsGSLs and impairs CD8 T cell activation. The impact of loss of SPPL3 and an elevated nsGSL profile in tumor cells on innate immune recognition remains to be elucidated. This study investigates the anti-tumor efficacy of neutrophils, NK cells, and γδ T cells on tumor cells lacking SPPL3. Our findings demonstrate that SPPL3-deficient target cells are less susceptible to trogocytosis by neutrophils and killing by NK cells and γδ T cells. Mechanistically, SPPL3 influences trogocytosis and γδ T cell instigated killing through modulation of nsGSL expression while SPPL3-mediated reduced killing by NK cells is nsGSL-independent. The nsGSL-dependent SPPL3 sensitivity depends on the proximity of surface receptor domains to the cell membrane and the affinity of receptor-ligand interactions as shown with various sets of defined antibodies. Thus, SPPL3 expression by tumor cells alters crosstalk with immune cells through the receptor-ligand interactome thereby driving escape not only from adaptive but also from innate immunity. These data underline the importance of investigating a potential synergism of GSL synthesis inhibitors with current immune cell activating immunotherapies.
HostingRepository	PRIDE
AnnounceDate	2025-09-30
AnnouncementXML	Submission_2025-09-30_00:27:21.083.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Floris van Alphen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-04 07:14:59	ID requested
⏵ 1	2025-09-30 00:27:22	announced

10.1002/eji.202451129;

Verkerk T, de Waard AA, Koomen SJI, Sanders J, Jorritsma T, Pappot AT, Zandhuis ND, Zhang T, Wuhrer M, Hoogendijk AJ, van Alphen FPJ, van den Biggelaar M, Stockinger HSJ, van Gisbergen KPJM, Spaapen RM, van Ham SM, Tumor-Expressed SPPL3 Supports Innate Antitumor Immune Responses. Eur J Immunol, 55(2):e202451129(2025) [pubmed]

submitter keyword: SPPL3, CD8 T-cells,anti-tumor response, B3GNT5

S. Marieke van Ham
contact affiliation	Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
contact email	M.vanham@sanquin.nl
lab head
Floris van Alphen
contact affiliation	Sanquin Research
contact email	f.vanalphen@sanquin.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056501
     1. Label: PRIDE project
     2. Name: Tumor-expressed SPPL3 supports innate anti-tumor immune responses