TY - JOUR
T1 - Quantitative phosphoproteomic analysis reveals involvement of PD-1 in multiple T cell functions
AU - Tocheva, Anna S.
AU - Peled, Michael
AU - Strazza, Marianne
AU - Adam, Kieran R.
AU - Lerrer, Shalom
AU - Nayak, Shruti
AU - Azoulay-Alfaguter, Inbar
AU - Foster, Connor J.R.
AU - Philips, Elliot A.
AU - Neel, Benjamin G.
AU - Ueberheide, Beatrix
AU - Mor, Adam
N1 - Publisher Copyright:
© 2020 Tocheva et al.
PY - 2020/12/25
Y1 - 2020/12/25
N2 - Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches.
AB - Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches.
UR - http://www.scopus.com/inward/record.url?scp=85098244457&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA120.014745
DO - 10.1074/jbc.RA120.014745
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C2 - 33077516
AN - SCOPUS:85098244457
SN - 0021-9258
VL - 295
SP - 18036
EP - 18050
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -