02 July 2020

Deceive the deceiver

Researchers from Yale University have discovered a "jamming signal" that blocks a powerful stimulator of the immune system – the protein interleukin-18 (IL-18), which is activated when atypical cells appear. Overcoming this block may enhance the immunotherapy of tumors resistant to existing treatment. The research team created a version of IL-18 that cannot be silenced, which significantly reduced tumors in mice resistant to conventional immunotherapy.

IL-18 is a pro-inflammatory cytokine, it plays a special role in the mobilization of T cells and natural T-killers to fight infections. Pharmaceutical companies have previously tried to use IL-18 to treat cancer, but this approach has not shown any effectiveness in clinical trials.

Aaron Ring and his colleagues suggested that the paradox of the ineffectiveness of IL-18 therapy lies in some immunological countermeasures used by cancer cells. They found that many forms of cancer have elevated levels of interleukin-18-binding protein (IL-18BP), which acts as a "decoy receptor", blocking the ability of IL-18 to bind to its receptor on immune cells and activate the immune response. The group decided to create a synthetic version of IL-18 that could overcome the effects of IL-18BP.

Using the process of directed evolution, Ring and his colleagues searched for about 300 million different mutant forms of IL-18 to find rare variants that always bind to the real IL-18 receptor, and not to the bait.

The researchers injected synthetic IL-18 into mice with various types of tumors, including those resistant to conventional immunotherapy. They found that the therapy resulted in a significant reduction in growth or completely destroyed tumors in many mice. Subsequent analysis showed that synthetic IL-18 increased the number of stem-like T cells that support effective antitumor responses.

The existing approved immunotherapy is very successful in the fight against so-called "hot" tumors, which are characterized by the presence of inflammation. However, "cold" tumors, in which there is no immune activity, do not respond to immunotherapy. The authors write that since synthetic IL-18 can affect cells of the innate immune system, such as natural T-killers, it has the potential to be effective against "cold" tumors.

Ring plans to start clinical trials of the drug next year.

Article T.Zhou et al. IL-18BP is a secret immune checkpoint and barrier to IL-18 immunotherapy published in the journal Nature.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru according to YaleNews: Blocking a 'jamming signal' can unleash immune system to fight tumors.

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