IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors

Elham Beyranvand Nejad, Camilla Labrie, Marit J. Van Elsas, Jan Willem Kleinovink, Hans Willi Mittrücker, Kees L.M.C. Franken, Sylvia Heink, Thomas Korn, Ramon Arens, Thorbald Van Hall, Sjoerd H. Van Der Burg

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 Il6ra fl/fl ×LysM cre+ 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 Il6ra fl/fl ×LysM cre+ 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.

Original languageEnglish
Article numbere002460
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number4
DOIs
StatePublished - 20 Apr 2021

Keywords

  • CD8-Positive T-Lymphocytes
  • active
  • adaptive immunity
  • immune evation
  • immunotherapy
  • macrophages

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