PMID- 34104540
OWN - NLM
STAT- MEDLINE
DCOM- 20210802
LR  - 20220107
IS  - 2162-402X (Electronic)
IS  - 2162-4011 (Print)
IS  - 2162-4011 (Linking)
VI  - 10
IP  - 1
DP  - 2021 May 24
TI  - Low-dose CDK4/6 inhibitors induce presentation of pathway specific MHC ligands as 
      potential targets for cancer immunotherapy.
PG  - 1916243
LID - 10.1080/2162402X.2021.1916243 [doi]
LID - 1916243
AB  - 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 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 
      proteins targeted by abemaciclib and palbociclib, were predicted to be the most 
      likely to induce a T cell response. 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 from G1/S phase transition, that have the highest 
      chance for being recognized by T cells, 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.
CI  - (c) 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
FAU - Charles, Angel
AU  - Charles A
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA.
FAU - Bourne, Christopher M
AU  - Bourne CM
AUID- ORCID: 0000-0001-9290-4223
AD  - Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, 
      USA.
FAU - Korontsvit, Tanya
AU  - Korontsvit T
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA.
FAU - Aretz, Zita E H
AU  - Aretz ZEH
AD  - Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, 
      USA.
FAU - Mun, Sung Soo
AU  - Mun SS
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA.
FAU - Dao, Tao
AU  - Dao T
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA.
FAU - Klatt, Martin G
AU  - Klatt MG
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA.
FAU - Scheinberg, David A
AU  - Scheinberg DA
AD  - Molecular Pharmacology Program, Sloan Kettering Institute, New York, USA.
AD  - Pharmacology Program, Weill Cornell Medicine, New York, USA.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - R01 CA055349/CA/NCI NIH HHS/United States
GR  - R35 CA241894/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210524
PL  - United States
TA  - Oncoimmunology
JT  - Oncoimmunology
JID - 101570526
RN  - 0 (Ligands)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.22 (CDK4 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 6)
SB  - IM
MH  - Cyclin-Dependent Kinase 4
MH  - *Cyclin-Dependent Kinase 6
MH  - Humans
MH  - Immunotherapy
MH  - Ligands
MH  - *Neoplasms
MH  - Protein Kinase Inhibitors
PMC - PMC8158036
OTO - NOTNLM
OT  - CDK4/6
OT  - HLA ligandome
OT  - abemaciclib
OT  - antigen presentation
OT  - breast cancer
OT  - cell cycle
OT  - combination therapeutics
OT  - immuntherapy
OT  - mass spectometry
OT  - palbociclib
EDAT- 2021/06/10 06:00
MHDA- 2021/08/03 06:00
PMCR- 2021/05/24
CRDT- 2021/06/09 06:48
PHST- 2021/06/09 06:48 [entrez]
PHST- 2021/06/10 06:00 [pubmed]
PHST- 2021/08/03 06:00 [medline]
PHST- 2021/05/24 00:00 [pmc-release]
AID - 1916243 [pii]
AID - 10.1080/2162402X.2021.1916243 [doi]
PST - epublish
SO  - Oncoimmunology. 2021 May 24;10(1):1916243. doi: 10.1080/2162402X.2021.1916243.