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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Published in:	International journal of molecular sciences Vol. 22; no. 21; p. 11848
Main Authors:	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
Language:	English
Published:	Switzerland MDPI AG 31.10.2021 MDPI
Subjects:	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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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.
AbstractList	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. 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.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.
Author	Fennell, Christie Jane Akue, Adovi KuKuruga, Mark A. Zhu, Christina Bacot, Silvia M. Wang, Tao Matthews, Rebecca L. Yue, Peng Benton, Alexander Feldman, Gerald M. Harper, Taylor A. Friedman, Devira Lee, Shiowjen
AuthorAffiliation	2 Office of Vaccines Research & Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Adovi.Akue@fda.hhs.gov (A.A.); Mark.Kukuruga@fda.hhs.gov (M.A.K.); Shiowjen.Lee@fda.hhs.gov (S.L.) 1 Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; tah9h@virginia.edu (T.A.H.); Silvia.Bacot@fda.hhs.gov (S.M.B.); ChristieJane.Fennell@fda.hhs.gov (C.J.F.); rebecca.matthews@nih.gov (R.L.M.); Christina.Zhu@fda.hhs.gov (C.Z.); shandongyuepeng@hotmail.com (P.Y.); alexander.benton@okstate.edu (A.B.); dsf2141@barnard.edu (D.F.)
AuthorAffiliation_xml	– name: 2 Office of Vaccines Research & Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA; Adovi.Akue@fda.hhs.gov (A.A.); Mark.Kukuruga@fda.hhs.gov (M.A.K.); Shiowjen.Lee@fda.hhs.gov (S.L.) – name: 1 Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; tah9h@virginia.edu (T.A.H.); Silvia.Bacot@fda.hhs.gov (S.M.B.); ChristieJane.Fennell@fda.hhs.gov (C.J.F.); rebecca.matthews@nih.gov (R.L.M.); Christina.Zhu@fda.hhs.gov (C.Z.); shandongyuepeng@hotmail.com (P.Y.); alexander.benton@okstate.edu (A.B.); dsf2141@barnard.edu (D.F.)
Author_xml	– sequence: 1 givenname: Taylor A. orcidid: 0000-0002-6088-1028 surname: Harper fullname: Harper, Taylor A. – sequence: 2 givenname: Silvia M. surname: Bacot fullname: Bacot, Silvia M. – sequence: 3 givenname: Christie Jane orcidid: 0000-0002-2229-6848 surname: Fennell fullname: Fennell, Christie Jane – sequence: 4 givenname: Rebecca L. surname: Matthews fullname: Matthews, Rebecca L. – sequence: 5 givenname: Christina surname: Zhu fullname: Zhu, Christina – sequence: 6 givenname: Peng surname: Yue fullname: Yue, Peng – sequence: 7 givenname: Alexander orcidid: 0000-0002-4421-0179 surname: Benton fullname: Benton, Alexander – sequence: 8 givenname: Devira surname: Friedman fullname: Friedman, Devira – sequence: 9 givenname: Adovi surname: Akue fullname: Akue, Adovi – sequence: 10 givenname: Mark A. surname: KuKuruga fullname: KuKuruga, Mark A. – sequence: 11 givenname: Shiowjen surname: Lee fullname: Lee, Shiowjen – sequence: 12 givenname: Tao orcidid: 0000-0002-1153-3430 surname: Wang fullname: Wang, Tao – sequence: 13 givenname: Gerald M. surname: Feldman fullname: Feldman, Gerald M.
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Keywords	STAT3 pathway nivolumab AKT serine–threonine kinase pathway MAP kinase pathway cytokines T cells interleukin 10
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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.
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Snippet	Immune checkpoint inhibitor (ICI) therapy has revolutionized anti-cancer treatment for many late-stage cancer patients. However, ICI therapy has thus far...
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SubjectTerms	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
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
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