PXD024965-1

PXD024965 is an original dataset announced via ProteomeXchange.

Title	Low-Dose CDK4/6 Inhibitors Induce Presentation of Pathway Specific MHC ligands as Potential Targets for Cancer Immunotherapy
Description	Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) lead to cell-cycle arrest but also trigger T cell-mediated immunity, which might be mediated by the qualitative and quantitative changes in human leukocyte antigen (HLA) ligands on the cancer cell surface. We investigated the effects of CDK4/6i, Abemaciclib and Palbociclib, on the immunopeptidome at subclinical, non-toxic, levels in breast cancer cell lines by biochemical isolation and identification of HLA ligands followed by network analyses. This treatment led to upregulation of cell surface HLA and revealed hundreds of induced HLA ligands in breast cancer cell lines. These new ligands were significantly enriched for peptides derived from proteins involved in the “G1/S phase transition of cell cycle” including HLA ligands from CDK4/6, Cyclin D1 and the 26S regulatory proteasomal subunit 4 (PSMC1). Interestingly, peptides from this essential biological process, that is targeted by Abemaciclib and Palbociclib, were predicted to be the most likely to induce a T cell response within the group of all induced HLA ligands when compared to HLA ligands from the DMSO-treated group. In strong contrast, peptides induced by solely one of the drugs had a lower T cell recognition score compared to the DMSO control suggesting that the observed effect is class dependent. This general hypothesis was exemplified by a peptide from PSMC1 which was among the HLA ligands with highest prediction scores and which elicited a T cell response in healthy donors. Overall, these data demonstrate that CDK4/6i treatment gives rise to drug-induced HLA ligands, that have the highest chance for being recognized by T cells if they are derived from the inhibited process of G1/S phase transition, thus providing evidence that inhibition of a distinct cellular process leads to increased presentation of the involved proteins that may be targeted by immunotherapeutic agents.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-16_23:55:41.605.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martin Klatt
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; acetylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-23 23:37:11	ID requested
⏵ 1	2022-02-16 23:55:42	announced

Charles A, Bourne CM, Korontsvit T, Aretz ZEH, Mun SS, Dao T, Klatt MG, Scheinberg DA, Low-dose CDK4/6 inhibitors induce presentation of pathway specific MHC ligands as potential targets for cancer immunotherapy. Oncoimmunology, 10(1):1916243(2021) [pubmed]

submitter keyword: Breast Cancer, MHC Ligand, CDK4/6 Inhibition, Palbociclib, Abemaciclib

David A. Scheinberg
contact affiliation	Memorial Sloan Kettering Cancer Center Department of Molecular Pharmacology
contact email	scheinbd@mkscc.org
lab head
Martin Klatt
contact affiliation	MSKCC
contact email	martin.g.klatt@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024965
     1. Label: PRIDE project
     2. Name: Low-Dose CDK4/6 Inhibitors Induce Presentation of Pathway Specific MHC ligands as Potential Targets for Cancer Immunotherapy