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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MDPI AG
2021
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oai:doaj.org-article:593e5988af814e43a4f69208f2a1b7c82021-11-11T17:16:32ZIL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses10.3390/ijms2221118481422-00671661-6596https://doaj.org/article/593e5988af814e43a4f69208f2a1b7c82021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11848https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Immune 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.Taylor A. HarperSilvia M. BacotChristie Jane FennellRebecca L. MatthewsChristina ZhuPeng YueAlexander BentonDevira FriedmanAdovi AkueMark A. KuKurugaShiowjen LeeTao WangGerald M. FeldmanMDPI AGarticlenivolumabinterleukin 10T cellscytokinesSTAT3 pathwayAKT serine–threonine kinase pathwayBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11848, p 11848 (2021) |
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EN |
| topic |
nivolumab interleukin 10 T cells cytokines STAT3 pathway AKT serine–threonine kinase pathway Biology (General) QH301-705.5 Chemistry QD1-999 |
| spellingShingle |
nivolumab interleukin 10 T cells cytokines STAT3 pathway AKT serine–threonine kinase pathway Biology (General) QH301-705.5 Chemistry QD1-999 Taylor A. Harper Silvia M. Bacot Christie Jane Fennell Rebecca L. Matthews Christina Zhu Peng Yue Alexander Benton Devira Friedman Adovi Akue Mark A. KuKuruga Shiowjen Lee Tao Wang Gerald M. Feldman IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses |
| description |
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. |
| format |
article |
| author |
Taylor A. Harper Silvia M. Bacot Christie Jane Fennell Rebecca L. Matthews Christina Zhu Peng Yue Alexander Benton Devira Friedman Adovi Akue Mark A. KuKuruga Shiowjen Lee Tao Wang Gerald M. Feldman |
| author_facet |
Taylor A. Harper Silvia M. Bacot Christie Jane Fennell Rebecca L. Matthews Christina Zhu Peng Yue Alexander Benton Devira Friedman Adovi Akue Mark A. KuKuruga Shiowjen Lee Tao Wang Gerald M. Feldman |
| author_sort |
Taylor A. Harper |
| title |
IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses |
| title_short |
IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses |
| title_full |
IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses |
| title_fullStr |
IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses |
| title_full_unstemmed |
IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses |
| title_sort |
il-10 signaling elicited by nivolumab-induced activation of the map kinase pathway does not fully contribute to nivolumab-modulated heterogeneous t cell responses |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/593e5988af814e43a4f69208f2a1b7c8 |
| work_keys_str_mv |
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