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Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses

PD-1 expression marks activated T cells susceptible to PD-1–mediated inhibition but not whether a PD-1–mediated signal is being delivered. Molecular predictors of response to PD-1 immune checkpoint blockade (ICB) are needed. We describe a monoclonal antibody (mAb) that detects PD-1 signaling through...

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Autores principales: Bu, Xia, Juneja, Vikram R., Reynolds, Carol G., Mahoney, Kathleen M., Bu, Melissa T., McGuire, Kathleen A., Maleri, Seth, Hua, Ping, Zhu, Baogong, Klein, Sarah R., Greenfield, Edward A., Armand, Philippe, Ritz, Jerome, Sharpe, Arlene H., Freeman, Gordon J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642283/
https://www.ncbi.nlm.nih.gov/pubmed/34635486
http://dx.doi.org/10.1158/2326-6066.CIR-21-0493
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author Bu, Xia
Juneja, Vikram R.
Reynolds, Carol G.
Mahoney, Kathleen M.
Bu, Melissa T.
McGuire, Kathleen A.
Maleri, Seth
Hua, Ping
Zhu, Baogong
Klein, Sarah R.
Greenfield, Edward A.
Armand, Philippe
Ritz, Jerome
Sharpe, Arlene H.
Freeman, Gordon J.
author_facet Bu, Xia
Juneja, Vikram R.
Reynolds, Carol G.
Mahoney, Kathleen M.
Bu, Melissa T.
McGuire, Kathleen A.
Maleri, Seth
Hua, Ping
Zhu, Baogong
Klein, Sarah R.
Greenfield, Edward A.
Armand, Philippe
Ritz, Jerome
Sharpe, Arlene H.
Freeman, Gordon J.
author_sort Bu, Xia
collection PubMed
description PD-1 expression marks activated T cells susceptible to PD-1–mediated inhibition but not whether a PD-1–mediated signal is being delivered. Molecular predictors of response to PD-1 immune checkpoint blockade (ICB) are needed. We describe a monoclonal antibody (mAb) that detects PD-1 signaling through the detection of phosphorylation of the immunotyrosine switch motif (ITSM) in the intracellular tail of mouse and human PD-1 (phospho–PD-1). We showed PD-1(+) tumor-infiltrating lymphocytes (TILs) in MC38 murine tumors had high phosphorylated PD-1, particularly in PD-1(+)TIM-3(+) TILs. Upon PD-1 blockade, PD-1 phosphorylation was decreased in CD8(+) TILs. Phospho–PD-1 increased in T cells from healthy human donors after PD-1 engagement and decreased in patients with Hodgkin lymphoma following ICB. These data demonstrate that phosphorylation of the ITSM motif of PD-1 marks dysfunctional T cells that may be rescued with PD-1 blockade. Detection of phospho–PD-1 in TILs is a potential biomarker for PD-1 immunotherapy responses.
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spelling pubmed-86422832022-06-01 Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses Bu, Xia Juneja, Vikram R. Reynolds, Carol G. Mahoney, Kathleen M. Bu, Melissa T. McGuire, Kathleen A. Maleri, Seth Hua, Ping Zhu, Baogong Klein, Sarah R. Greenfield, Edward A. Armand, Philippe Ritz, Jerome Sharpe, Arlene H. Freeman, Gordon J. Cancer Immunol Res Research Articles PD-1 expression marks activated T cells susceptible to PD-1–mediated inhibition but not whether a PD-1–mediated signal is being delivered. Molecular predictors of response to PD-1 immune checkpoint blockade (ICB) are needed. We describe a monoclonal antibody (mAb) that detects PD-1 signaling through the detection of phosphorylation of the immunotyrosine switch motif (ITSM) in the intracellular tail of mouse and human PD-1 (phospho–PD-1). We showed PD-1(+) tumor-infiltrating lymphocytes (TILs) in MC38 murine tumors had high phosphorylated PD-1, particularly in PD-1(+)TIM-3(+) TILs. Upon PD-1 blockade, PD-1 phosphorylation was decreased in CD8(+) TILs. Phospho–PD-1 increased in T cells from healthy human donors after PD-1 engagement and decreased in patients with Hodgkin lymphoma following ICB. These data demonstrate that phosphorylation of the ITSM motif of PD-1 marks dysfunctional T cells that may be rescued with PD-1 blockade. Detection of phospho–PD-1 in TILs is a potential biomarker for PD-1 immunotherapy responses. American Association for Cancer Research 2021-12-01 2021-10-11 /pmc/articles/PMC8642283/ /pubmed/34635486 http://dx.doi.org/10.1158/2326-6066.CIR-21-0493 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Research Articles
Bu, Xia
Juneja, Vikram R.
Reynolds, Carol G.
Mahoney, Kathleen M.
Bu, Melissa T.
McGuire, Kathleen A.
Maleri, Seth
Hua, Ping
Zhu, Baogong
Klein, Sarah R.
Greenfield, Edward A.
Armand, Philippe
Ritz, Jerome
Sharpe, Arlene H.
Freeman, Gordon J.
Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
title Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
title_full Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
title_fullStr Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
title_full_unstemmed Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
title_short Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
title_sort monitoring pd-1 phosphorylation to evaluate pd-1 signaling during antitumor immune responses
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642283/
https://www.ncbi.nlm.nih.gov/pubmed/34635486
http://dx.doi.org/10.1158/2326-6066.CIR-21-0493
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