Dataset Information

Low-Dose CDK4/6 Inhibitors Induce Presentation of Pathway Specific MHC ligands as Potential Targets for Cancer Immunotherapy

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Martin Klatt

LAB HEAD: David A. Scheinberg

PROVIDER: PXD024965 | Pride | 2021-09-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MS195454LUM_martin_scheinberg_MCF7_Abemaciclib.raw	Raw
	MS195454LUM_martin_scheinberg_MCF7_DMSO.raw	Raw
	MS195454LUM_martin_scheinberg_MCF_Palbociclib.raw	Raw
	MS205868LUM_martin_scheinberg_MCF7_Abemaciclib_b.raw	Raw
	MS205868LUM_martin_scheinberg_T47D_DMSO_a.raw	Raw

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Publications

Low-dose CDK4/6 inhibitors induce presentation of pathway specific MHC ligands as potential targets for cancer immunotherapy.

Charles Angel A Bourne Christopher M CM Korontsvit Tanya T Aretz Zita E H ZEH Mun Sung Soo SS Dao Tao T Klatt Martin G MG Scheinberg David A DA

Oncoimmunology 20210524 1

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 changes in human leukocyte antigen (HLA) ligands. We investigated the effects of CDK4/6i, abemaciclib and palbociclib, on the immunopeptidome at nontoxic levels in breast cancer cell lines by biochemical identification of HLA ligands followed by network analyses. This treatment led to upregulation of HLA and revealed hundreds of induced HLA ligands in b ...[more]

PMID: 34104540

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