Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the pri...

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Published in:International journal of molecular sciences Vol. 21; no. 23; p. 9023
Main Authors: Bacot, Silvia M., Harper, Taylor A., Matthews, Rebecca L., Fennell, Christie Jane, Akue, Adovi, KuKuruga, Mark A., Lee, Shiowjen, Wang, Tao, Feldman, Gerald M.
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 27.11.2020
MDPI
Subjects:
Antigens, CD - metabolism
Biomarkers
Biomarkers - metabolism
Cancer
Cell Proliferation - drug effects
Cytokines
Cytokines - biosynthesis
Cytomegalovirus
Deoxyribonucleic acid
DNA
FDA approval
Flow cytometry
Granzymes - metabolism
Humans
Immunoassay
Immunotherapy
Leukocytes, Mononuclear - metabolism
Lymphocyte Activation - drug effects
Lymphocytes
Mutation
Nivolumab - pharmacology
Patients
Programmed Cell Death 1 Receptor - metabolism
T cell receptors
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Targeted cancer therapy
Th1 Cells - immunology
Tissue Donors
peripheral blood mononuclear cells
cytokines
T cells
biomarker
Nivolumab
ISSN:1422-0067, 1661-6596, 1422-0067
Online Access:Get full text
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Summary:The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy.
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Current address: Cancer ImmunoPrevention Laboratory, Vaccine, Immunity, and Cancer Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Current address: Flow Cytometry Core Facility, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA.
These authors contributed equally to this paper.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21239023