SHP2 Targets ITK Downstream of PD-1 to Inhibit T Cell Function.
Animals
Cell Line, Tumor
Humans
Jurkat Cells
Mice
Piperidines
/ pharmacology
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ antagonists & inhibitors
Protein-Tyrosine Kinases
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
T-Lymphocytes
/ drug effects
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
/ methods
ITK
PD-1
SHP2
T cell receptor
Journal
Inflammation
ISSN: 1573-2576
Titre abrégé: Inflammation
Pays: United States
ID NLM: 7600105
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
30
11
2020
accepted:
08
02
2021
revised:
28
01
2021
pubmed:
25
2
2021
medline:
24
12
2021
entrez:
24
2
2021
Statut:
ppublish
Résumé
PD-1 is a critical therapeutic target in cancer immunotherapy and antibodies blocking PD-1 are approved for multiple types of malignancies. The phosphatase SHP2 is the main effector mediating PD-1 downstream signaling and accordingly attempts have been made to target this enzyme as an alternative approach to treat immunogenic tumors. Unfortunately, small molecule inhibitors of SHP2 do not work as expected, suggesting that the role of SHP2 in T cells is more complex than initially hypothesized. To better understand the perplexing role of SHP2 in T cells, we performed interactome mapping of SAP, an adapter protein that is associated with SHP2 downstream signaling. Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. This study suggests that ITK is a unique target in this pathway, and since ITK is a SHP2-dependent specific mediator of PD-1 signaling, the combination of ITK inhibitors with PD-1 blockade may improve upon PD-1 monotherapy in the treatment of cancer.
Identifiants
pubmed: 33624224
doi: 10.1007/s10753-021-01437-8
pii: 10.1007/s10753-021-01437-8
pmc: PMC9199348
mid: NIHMS1696709
doi:
Substances chimiques
PDCD1 protein, human
0
Piperidines
0
Programmed Cell Death 1 Receptor
0
Pyrimidines
0
SHP099
0
Protein-Tyrosine Kinases
EC 2.7.10.1
emt protein-tyrosine kinase
EC 2.7.10.2
PTPN11 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1529-1539Subventions
Organisme : NIAID NIH HHS
ID : R01 AI125640
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA231277
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150597
Pays : United States
Organisme : NIH HHS
ID : AI125640
Pays : United States
Organisme : National Institutes of Health (US)
ID : AI150597
Organisme : National Institutes of Health (US)
ID : CA231277
Organisme : NIH HHS
ID : AI125640
Pays : United States
Organisme : Cancer Research Institute
ID : N/A
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
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