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

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.

IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses

“…Our data show that the levels of IL-10 induced by nivolumab or pembrolizumab are highly heterogeneous. Consistent with this, our recent studies also showed that nivolumab induces IL-10 production using a PBMC-based assay [ 45 ]. This is consistent with a recent report that elevated IL-10 levels caused by anti-PD-1 mAb treatment were also found in an animal tumor model [ 25 ].…”

“…The mechanisms underlying these challenges are not fully understood [ 6 , 8 , 41 , 42 , 43 , 44 ]. IL-10 is one of the most important immunoregulatory cytokines that regulates the T cell response via modulating multiple signaling pathways [ 12 , 14 , 15 , 25 , 45 ]. In the present study, we describe that nivolumab induces potent IL-10 secretion in T cells due to activation of the MAPK pathway.…”

m6A Regulators Is Differently Expressed and Correlated With Immune Response of Esophageal Cancer

“…ICT with anti-PD-1 and anti-PD-L1 therapy has completely changed the treatment of various advanced cancers ( Bacot et al, 2020 ), including EC. Despite immune checkpoint inhibitors (ICI) can significantly improve the prognosis of patients with EC, there are still a considerable proportion of patients who have no response or resistance to ICT.…”

A subcutaneous abscess following anti‐programmed cell death 1/programmed death‐ligand 1 antibody treatment for lung cancer

“…Consistently, foreign body reaction is mediated by Th17 cells, 6 whose reaction can be enhanced by immune checkpoint inhibitor. 7 Several cases showed an immune reaction to nonabsorbent surgical sutures, leading to abscess formation 8 ; therefore, the enhancement of immune reaction by immune checkpoint inhibitors might develop a foreign body reaction to a nonabsorbent surgical suture. The second reason was a reaction to the scar after the appendectomy.…”