IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy

Nature. 2020 Jul;583(7817):609-614. doi: 10.1038/s41586-020-2422-6. Epub 2020 Jun 24.

Abstract

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials3. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1+ precursor CD8+ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Disease Models, Animal
  • Female
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immunotherapy*
  • Intercellular Signaling Peptides and Proteins / immunology*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interleukin-18 / immunology*
  • Kaplan-Meier Estimate
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Lymphocytes, Tumor-Infiltrating / cytology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • Receptors, Interleukin-18 / metabolism
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Histocompatibility Antigens Class I
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • Receptors, Interleukin-18
  • interleukin-18 binding protein