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

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 recogni...

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Veröffentlicht in:International journal of molecular sciences Jg. 22; H. 21; S. 11848
Hauptverfasser: Harper, Taylor A., Bacot, Silvia M., Fennell, Christie Jane, Matthews, Rebecca L., Zhu, Christina, Yue, Peng, Benton, Alexander, Friedman, Devira, Akue, Adovi, KuKuruga, Mark A., Lee, Shiowjen, Wang, Tao, Feldman, Gerald M.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland MDPI AG 31.10.2021
MDPI
Schlagworte:
Apoptosis
Cancer
Clinical trials
Cytokines
FDA approval
Humans
Immunotherapy
Interferon-gamma - immunology
Interleukin-10 - immunology
Interleukin-2 Receptor alpha Subunit - immunology
Ki-67 Antigen - immunology
Lymphocyte Activation - drug effects
Lymphocytes
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - immunology
Melanoma
Nivolumab - pharmacology
T-Lymphocytes - immunology
Targeted cancer therapy
STAT3 pathway
nivolumab
AKT serine–threonine kinase pathway
MAP kinase pathway
cytokines
T cells
interleukin 10
ISSN:1422-0067, 1661-6596, 1422-0067
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Zusammenfassung: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.
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Present Affiliation: Department of Biochemistry, Oklahoma State University, Stillwater, OK 74075, USA.
Present Affiliation: Flow Cytometry Core Facility, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA.
Present Affiliation: Department of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Present Affiliation: Cancer ImmunoPrevention Laboratory, Vaccine, Immunity, and Cancer Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Present Affiliation: Barnard College, New York, NY 10027, USA.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms222111848