IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model

Cancer Immunol Immunother. 2017 Nov;66(11):1485-1496. doi: 10.1007/s00262-017-2043-6. Epub 2017 Jul 21.

Abstract

Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.

Keywords: Anti-OX40 Ab; CD8; CpG ODN; IL-4; Macrophages.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / immunology
  • Immunotherapy / methods*
  • Interleukin-4 / antagonists & inhibitors*
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Macrophages / classification
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy*
  • Oligodeoxyribonucleotides / immunology
  • Oligodeoxyribonucleotides / pharmacology
  • Receptors, OX40 / antagonists & inhibitors
  • Receptors, OX40 / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Time Factors
  • Treatment Outcome
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Tumor Burden / immunology
  • Tumor Microenvironment / drug effects*
  • Tumor Microenvironment / immunology

Substances

  • Antibodies, Neutralizing
  • CPG-oligonucleotide
  • Oligodeoxyribonucleotides
  • Receptors, OX40
  • Interleukin-4