PXD054820

PXD054820 is an original dataset announced via ProteomeXchange.

Title	Inhibition of Cbl-b restores effector functions of human intratumoral NK cells
Description	Background: T cell-based immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells can induce durable responses in cancer patients. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of Natural Killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their Major Histocompatibility Complex class I (MHC I) expression due to acquired resistance mechanisms. However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy. Method: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compound on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated utilizing compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types. Results: The screening approach led to the identification of a Cbl-b inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with TIGIT blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells. Conclusion: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cells dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for cancer patients.
HostingRepository	MassIVE
AnnounceDate	2024-11-07
AnnouncementXML	Submission_2024-11-07_06:55:35.711.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Katarzyna Buczak
SpeciesList	scientific name: human;
ModificationList	Carbamidomethyl
Instrument	instrument model

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-12 11:50:37	ID requested
⏵ 1	2024-11-07 06:55:36	announced

no publication

submitter keyword: NK dysfunction, cancer immunotherapy, Cbl-b inhibitor, MHC I loss

Alfred Zippelius
contact affiliation	University of Basel
contact email	alfred.zippelius@unibas.ch
lab head
Katarzyna Buczak
contact affiliation	Biozentrum, University of Basel
contact email	katarzyna.buczak@unibas.ch
dataset submitter

MassIVE dataset URI

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