Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 11, 2021
- Source ID
- 10.1158/2326-6066.cir-21-0493
Entities
People
- Arlene Sharpe
- Baogong Zhu
- Carol G. Reynolds
- Edward A. Greenfield
- Gordon J. Freeman
- Jerome Ritz
- Kathleen A. Mcguire
- Kathleen M Mahoney
- Melissa T. Bu
- Philippe Armand
- Ping Hua
- Sarah R. Klein
- Seth Maleri
- Vikram R. Juneja
- Xia Bu
Organizations
- American Association for Cancer Research
- Cancer Research Foundation
- Harvard Medical School
- Kidney Cancer Association
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Science Foundation