The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors

Abstract

Recently, the overall survival (OS) and progression-free survival (PFS) of patients with advanced cancer has been significantly improved due to the application of immune checkpoint inhibitors (ICIs). Low response rate and high occurrence of immune-related adverse events (irAEs) make urgently need for ideal predictive biomarkers to identity efficient population and guide treatment strategies. Cytokines are small soluble proteins with a wide range of biological activity that are secreted by activated immune cells or tumor cells and act as a bridge between innate immunity, infection, inflammation and cancer. Cytokines can be detected in peripheral blood and suitable for dynamic detection. During the era of ICIs, many studies investigated the role of cytokines in prediction of the efficiency and toxicity of ICIs. Herein, we review the relevant studies on TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as biomarkers for predicting ICI-related reactions and adverse events, and explore the immunomodulatory mechanisms. Finally, the most important purpose of this review is to help identify predictors of ICI to screen patients who are most likely to benefit from immunotherapy.

Keywords: adverse events; cytokines; immune checkpoint inhibitors; predictive factors; response.

Figure 1

Potential mechanisms of IFN-γ predicting the prognosis of ICIs. The production of IFN-γ induces the increase of chemokine CXCL9 and CXCL10, which recruits more tumor reactive T cells and increased the level of IFN-γ. IFN-γ released by T cells stimulates neighboring dendritic cells (DCs) to produce IL-12, which in turn promotes the production of IFN-γ and forms a positive feedback loop. IFN- γ induces LAG3 which mainly express on dysfunctional or depleted T cells and induce immunosuppression. The fragility of Treg driven by IFN-γ produced by intratumoral Nrp1-/- treg limits the activity of CD4+Treg cells.