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

J Immunother Cancer. 2021 Apr;9(4):e002460. doi: 10.1136/jitc-2021-002460.

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 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.

Keywords: CD8-Positive T-Lymphocytes; active; adaptive immunity; immune evation; immunotherapy; macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / drug effects
  • Female
  • Injections, Subcutaneous
  • Interleukin-6 / metabolism*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Oligodeoxyribonucleotides / administration & dosage*
  • Oligodeoxyribonucleotides / immunology
  • Papillomavirus E7 Proteins / administration & dosage*
  • Papillomavirus E7 Proteins / immunology
  • Phenotype
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction
  • Tumor Burden / drug effects
  • Tumor-Associated Macrophages / drug effects*
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism

Substances

  • Cancer Vaccines
  • CpG ODN 1826
  • Il6ra protein, mouse
  • Interleukin-6
  • Oligodeoxyribonucleotides
  • Papillomavirus E7 Proteins
  • Receptors, Interleukin-6
  • interleukin-6, mouse
  • oncogene protein E7, Human papillomavirus type 16