2. Academic Validation
  3. Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses

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

  • Cancer Immunol Res. 2021 Dec;9(12):1465-1475. doi: 10.1158/2326-6066.CIR-21-0493.
Xia Bu # 1,  Vikram R Juneja # 2 3 4,  Carol G Reynolds 1,  Kathleen M Mahoney 1,  Melissa T Bu 1,  Kathleen A McGuire 3 4,  Seth Maleri 3 4,  Ping Hua 1,  Baogong Zhu 1,  Sarah R Klein 1,  Edward A Greenfield 1,  Philippe Armand 1,  Jerome Ritz 1,  Arlene H Sharpe # 3 4,  Gordon J Freeman # 5
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • 2 Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts.
  • 3 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
  • 4 Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts. gordon_freeman@dfci.harvard.edu.
  • # Contributed equally.
PMID: 34635486 DOI: 10.1158/2326-6066.CIR-21-0493
Abstract

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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