Combination Approaches to Target PD-1 Signaling in Cancer.
ITK
PD-1
PD-L1
SHP2
T cell
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2022
2022
Historique:
received:
24
04
2022
accepted:
23
06
2022
entrez:
1
8
2022
pubmed:
2
8
2022
medline:
3
8
2022
Statut:
epublish
Résumé
Cancer remains the second leading cause of death in the US, accounting for 25% of all deaths nationwide. Immunotherapy techniques bolster the immune cells' ability to target malignant cancer cells and have brought immense improvements in the field of cancer treatments. One important inhibitory protein in T cells, programmed cell death protein 1 (PD-1), has become an invaluable target for cancer immunotherapy. While anti-PD-1 antibody therapy is extremely successful in some patients, in others it fails or even causes further complications, including cancer hyper-progression and immune-related adverse events. Along with countless translational studies of the PD-1 signaling pathway, there are currently close to 5,000 clinical trials for antibodies against PD-1 and its ligand, PD-L1, around 80% of which investigate combinations with other therapies. Nevertheless, more work is needed to better understand the PD-1 signaling pathway and to facilitate new and improved evidence-based combination strategies. In this work, we consolidate recent discoveries of PD-1 signaling mediators and their therapeutic potential in combination with anti-PD-1/PD-L1 agents. We focus on the phosphatases SHP2 and PTPN2; the kinases ITK, VRK2, GSK-3, and CDK4/6; and the signaling adaptor protein PAG. We discuss their biology both in cancer cells and T cells, with a focus on their role in relation to PD-1 to determine their potential in therapeutic combinations. The literature discussed here was obtained from a search of the published literature and ClinicalTrials.gov with the following key terms: checkpoint inhibition, cancer immunotherapy, PD-1, PD-L1, SHP2, PTPN2, ITK, VRK2, CDK4/6, GSK-3, and PAG. Together, we find that all of these proteins are logical and promising targets for combination therapy, and that with a deeper mechanistic understanding they have potential to improve the response rate and decrease adverse events when thoughtfully used in combination with checkpoint inhibitors.
Identifiants
pubmed: 35911672
doi: 10.3389/fimmu.2022.927265
pmc: PMC9330480
doi:
Substances chimiques
B7-H1 Antigen
0
Glycogen Synthase Kinase 3
EC 2.7.11.26
Protein Tyrosine Phosphatase, Non-Receptor Type 2
EC 3.1.3.48
Types de publication
Journal Article
Review
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
927265Subventions
Organisme : NCI NIH HHS
ID : F30 CA271624
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125640
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150597
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA231277
Pays : United States
Informations de copyright
Copyright © 2022 Moore, Strazza and Mor.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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