IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors
Background High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.Methods I...
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doaj-053008211eae4f6cb776e9ef21bcbc812021-09-27T16:00:04ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-04-019410.1136/jitc-2021-002460IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumorsSjoerd H van der Burg0Ramon Arens1Thorbald van Hall2Elham Beyranvand Nejad3Jan Willem Kleinovink4Camilla Labrie5Marit J van Elsas6Hans-Willi Mittrücker7Kees L M C Franken8Sylvia Heink9Thomas Korn10Medical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsMedical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsMedical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsMedical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsMedical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsMedical Oncology, Oncode institute, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsDepartment of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Immunology, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsExperimental Neuroimmunology, Technische Universität München, Munchen, Bayern, GermanyExperimental Neuroimmunology, Technische Universität München, Munchen, Bayern, GermanyBackground High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.Methods IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.control. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6rafl/fl×LysMcre+ mice.Results Our therapeutic vaccination protocol elicits a strong tumor-specific CD8+ T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8+ T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6rafl/fl×LysMcre+ but not cre-negative control mice, while no differences in the vaccine-induced CD8+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages.Conclusion IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections.https://jitc.bmj.com/content/9/4/e002460.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sjoerd H van der Burg Ramon Arens Thorbald van Hall Elham Beyranvand Nejad Jan Willem Kleinovink Camilla Labrie Marit J van Elsas Hans-Willi Mittrücker Kees L M C Franken Sylvia Heink Thomas Korn |
spellingShingle |
Sjoerd H van der Burg Ramon Arens Thorbald van Hall Elham Beyranvand Nejad Jan Willem Kleinovink Camilla Labrie Marit J van Elsas Hans-Willi Mittrücker Kees L M C Franken Sylvia Heink Thomas Korn IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors Journal for ImmunoTherapy of Cancer |
author_facet |
Sjoerd H van der Burg Ramon Arens Thorbald van Hall Elham Beyranvand Nejad Jan Willem Kleinovink Camilla Labrie Marit J van Elsas Hans-Willi Mittrücker Kees L M C Franken Sylvia Heink Thomas Korn |
author_sort |
Sjoerd H van der Burg |
title |
IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors |
title_short |
IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors |
title_full |
IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors |
title_fullStr |
IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors |
title_full_unstemmed |
IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors |
title_sort |
il-6 signaling in macrophages is required for immunotherapy-driven regression of tumors |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2021-04-01 |
description |
Background High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.Methods IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.control. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6rafl/fl×LysMcre+ mice.Results Our therapeutic vaccination protocol elicits a strong tumor-specific CD8+ T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8+ T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6rafl/fl×LysMcre+ but not cre-negative control mice, while no differences in the vaccine-induced CD8+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages.Conclusion IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections. |
url |
https://jitc.bmj.com/content/9/4/e002460.full |
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