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2018 ; 115
(3
): E468-E477
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Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new
checkpoint inhibitor
#MMPMID29282323
Peled M
; Tocheva AS
; Sandigursky S
; Nayak S
; Philips EA
; Nichols KE
; Strazza M
; Azoulay-Alfaguter I
; Askenazi M
; Neel BG
; Pelzek AJ
; Ueberheide B
; Mor A
Proc Natl Acad Sci U S A
2018[Jan]; 115
(3
): E468-E477
PMID29282323
show ga
Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells.
Antibodies targeting PD-1 elicit durable clinical responses in patients with
multiple tumor indications. Nevertheless, a significant proportion of patients do
not respond to anti-PD-1 treatment, and a better understanding of the signaling
pathways downstream of PD-1 could provide biomarkers for those whose tumors
respond and new therapeutic approaches for those whose tumors do not. We used
affinity purification mass spectrometry to uncover multiple proteins associated
with PD-1. Among these proteins, signaling lymphocytic activation
molecule-associated protein (SAP) was functionally and mechanistically analyzed
for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and
overexpression blocked PD-1 function. T cells from patients with X-linked
lymphoproliferative disease (XLP), who lack functional SAP, were hyperresponsive
to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly,
signaling downstream of PD-1 in purified T cell subsets did not correlate with
PD-1 surface expression but was inversely correlated with intracellular SAP
levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular
shield of key tyrosine residues that are targets for the tyrosine phosphatase
SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an
inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients
with XLP.
|Animals
[MESH]
|Biomarkers, Tumor
[MESH]
|Cell Cycle Checkpoints/*physiology
[MESH]
|Cell Proliferation/physiology
[MESH]
|Cytokines/genetics/metabolism
[MESH]
|Gene Expression Regulation, Enzymologic
[MESH]
|Gene Silencing
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Jurkat Cells
[MESH]
|Male
[MESH]
|Mass Spectrometry/*methods
[MESH]
|Mice
[MESH]
|Mice, Knockout
[MESH]
|Programmed Cell Death 1 Receptor/genetics/*metabolism
[MESH]
|Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/metabolism
[MESH]
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