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

Ting Zhou, William Damsky, Orr-El Weizman, Meaghan K. McGeary, K. Patricia Hartmann, Connor E. Rosen, Suzanne Fischer, Ruaidhri Jackson, Richard A. Flavell, Jun Wang, Miguel F. Sanmamed, Marcus W. Bosenberg and Aaron M. Ring ()
Additional contact information
Ting Zhou: Yale School of Medicine
William Damsky: Yale School of Medicine
Orr-El Weizman: Yale School of Medicine
Meaghan K. McGeary: Yale School of Medicine
K. Patricia Hartmann: Yale School of Medicine
Connor E. Rosen: Yale School of Medicine
Suzanne Fischer: Yale School of Medicine
Ruaidhri Jackson: Yale School of Medicine
Richard A. Flavell: Yale School of Medicine
Jun Wang: New York University Langone Medical Center
Miguel F. Sanmamed: Clínica Universidad de Navarra
Marcus W. Bosenberg: Yale School of Medicine
Aaron M. Ring: Yale School of Medicine

Nature, 2020, vol. 583, issue 7817, 609-614

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2422-6

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