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

Taylor A Harper,Devira Friedman,Rebecca L Matthews,Silvia M Bacot,Christie Jane Fennell,Peng Yue,Christina Zhu,Alexander Benton,Gerald M Feldman,Shiowjen Lee,Mark A Kukuruga,Adovi Akue,Tao Wang

doi:10.3390/ijms222111848

Abstract

Immune checkpoint inhibitor (ICI) therapy has revolutionized anti-cancer treatment for many late-stage cancer patients. However, ICI therapy has thus far demonstrated limited efficacy for most patients, and it remains unclear why this is so. Interleukin 10 (IL-10) is a cytokine that has been recognized as a central player in cancer biology with its ability to inhibit anti-tumor T cell responses. Recent studies suggest that IL-10 might also exert some intrinsic anti-tumor T cell responses, and clinical studies using recombinant IL-10 alone or in combination with ICI are underway. This paradoxical effect of IL-10 and its underlying mechanisms impacting ICI-modulated T cell responses remain poorly understood. In this study, using an in vitro mixed lymphocyte reaction assay, we found that treatment with ICIs such as the anti-programmed cell death receptor-1 (PD-1) mAb nivolumab elicits a strong expression of IL-10. While neutralization of IL-10 signaling with an anti-IL-10 specific mAb significantly decreases the production of IFN-γ by T cells in a cohort of donor cells, the opposite effect was observed in other donor cells. Similarly, neutralization of IL-10 signaling significantly decreases the expression of T cell activation markers Ki67 and CD25, as well as the production of Granzyme B in a cohort of donor cells, whereas the opposite effect was observed in others. Furthermore, we found that nivolumab and IL-10 differentially modulate the signal transducer and activator of transcription 3 (STAT3) and AKT serine–threonine kinase pathways. Finally, we found that nivolumab activates the mitogen-activated protein kinase (MAPK) pathway, which in turn is responsible for the observed induction of IL-10 production by nivolumab. These findings provide new insights into the mechanisms underlying anti-PD-1-modulated T cell responses by IL-10, which could lead to the discovery of novel combination treatments that target IL-10 and immune checkpoint molecules.

Highlights

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death receptor-1 (PD-1) and/or programmed cell death ligand-1 (PD-L1) therapeutic monoclonal antibodies reinvigorate the anti-tumor immunological activities by reversing immune checkpoint receptor-induced immunosuppressive effects [1,2,3,4]
In the current study, using a well-established Mixed Lymphocyte Reaction (MLR) assay that has been used for the characterization of nivolumab and pembrolizumab in nonclinical studies [30,31,32], we show that treatment with either nivolumab or pembrolizumab significantly increases Interleukin 10 (IL-10) production, concurrent with an increased production of the immune activation cytokine IFN-γ
One of many challenges for ICI immunotherapy is the low response rate coupled with patients who develop resistance to the therapy

Summary

Introduction

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death receptor-1 (PD-1) and/or programmed cell death ligand-1 (PD-L1) therapeutic monoclonal antibodies reinvigorate the anti-tumor immunological activities by reversing immune checkpoint receptor-induced immunosuppressive effects [1,2,3,4]. Identifying factors that drive or prevent an effective T cell response to ICI immunotherapy is an urgent need for understanding these resistance mechanisms, and could lead to the discovery of novel effective combination therapies. IL-10 has been recognized as one of the most important immunosuppressive cytokines, and accumulating evidence suggests that it has pleiotropic effects on immunoregulation and inflammation, as well as being one of the most critical modulators in anti-cancer immune responses [9,10,11]. Injection of PEGylated IL-10 into MMTV/HER2 transgenic mice led to tumor rejection that was dependent on activated CD8 T cells in an IFN-γ and Granzyme B-dependent manner [16]

Methods

Results

Conclusion