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Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E468-E477. doi: 10.1073/pnas.1710437115. Epub 2017 Dec 27.

Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor.

Author information

1
Department of Medicine, New York University School of Medicine, New York, NY 10016.
2
Proteomics Laboratory, Division of Advanced Research Technologies, New York University School of Medicine, New York, NY 10016.
3
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016.
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
5
Biomedical Hosting LLC, Arlington, MA 02474.
6
Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016.
7
Department of Medicine, New York University School of Medicine, New York, NY 10016; Adam.Mor@NYUMC.org.

Abstract

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.

KEYWORDS:

PD-1; SAP; SHP2; T cells; XLP

PMID:
29282323
PMCID:
PMC5776966
DOI:
10.1073/pnas.1710437115
[Indexed for MEDLINE]
Free PMC Article

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