Abstract
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.
Highlights
Immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 therapeutic antibodies like Nivolumab and Atezolizumab achieve remarkable benefits for many types of cancer, including melanoma and lung cancer, etc., identification of predictive biomarkers for anti-PD-1 therapy is one of the major challenges in developing effective immune checkpoint inhibitors (ICIs) therapies for cancer treatment
With the intent to identify potential parameters that respond to Nivolumab treatment, we focused on cytokine profiling due to the existence of reliable and robust cytokine assays which have potential in predicting the efficacy of anti-PD-1 immunotherapy
We found that anti-CD3 monoclonal antibody (mAb) stimulation induces expression of PD-1 in both CD4+ and CD8+ T cells in all tested donors (Supplementary Figure S1A,B)
Summary
Immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 therapeutic antibodies like Nivolumab and Atezolizumab achieve remarkable benefits for many types of cancer, including melanoma and lung cancer, etc., identification of predictive biomarkers for anti-PD-1 therapy is one of the major challenges in developing effective ICI therapies for cancer treatment. Ethical and technical challenges abound regarding the use of these two biomarkers in the clinic, such as requiring sufficient tumor material via invasive and inconvenient approaches, sampling biases that do not reflect tumor heterogeneity, lack of accuracy and reproducibility of laboratory protocols, and analysis of complex genomic alteration data of tumor samples, all of which significantly limit the implementation of these biomarkers in clinical practice [1,2,4] Neither of these biomarkers directly assesses treatment-induced T cell responses, which are thought to be the main mechanism of action of anti-PD1 therapy. We performed flow cytometry analyses to assess expression of the T cell proliferation marker Ki67, the expression of the activation markers CD69 and CD25, and the percentage of inducible CD4+CD25+FoxP3+ regulatory T cells
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