Abstract
IL18 engineered not to bind a decoy receptor, but not normal IL18, had antitumor efficacy in mice.
Major Finding: IL18 engineered not to bind a decoy receptor, but not normal IL18, had antitumor efficacy in mice.
Mechanism: Decoy-resistant IL18 remodeled the tumor microenvironment and stimulated tumor-infiltrating T cells.
Impact: IL18-based therapies, once restricted by low efficacy, may be useful anticancer agents when modified.
Cytokines have been investigated as anticancer immunotherapies, but their use has been limited by low efficacy. In the case of the proinflammatory cytokine IL18, this low efficacy may be attributable to high-affinity binding of IL18 to a decoy receptor called IL18 binding protein (IL18BP), the serum concentration of which is increased 10- to 100-fold upon treatment with recombinant IL18. To better understand this phenomenon and improve the efficacy of IL18-based anticancer treatments, Zhou, Damsky, Weizman, and colleagues first demonstrated that IL18BP expression was common in the tumor microenvironment in mice and patients. Using directed evolution, a decoy-resistant version of IL18 that retains the ability to bind the IL18 receptor was engineered. This decoy-resistant IL18 (but not normal IL18) inhibited tumor growth, increased survival, and in some cases caused complete tumor regression in mouse models of colorectal cancer and melanoma. The efficacy of this engineered IL18 variant was comparable or even superior to that of anti–PD-1, and combination treatment with both agents was synergistic, with most treated mice exhibiting complete tumor regression. Mechanistically, the efficacy of the decoy-resistant IL18 appeared to result from stimulation of tumor-infiltrating CD8+ T cells. Further investigation revealed that tumors from mice treated with the decoy-resistant IL18 had higher levels of T cells exhibiting an effector phenotype and lower levels of T cells exhibiting an exhausted phenotype compared with tumors from mice treated with normal IL18 or vehicle control. Additionally, tumors from mice treated with this engineered IL18 variant were enriched with more highly proliferative, polyfunctional T cells, which are thought to be important for robust antitumor immune response, as well as with stem-like CD8+ T cells critical for durable immunotherapy responses. Decoy-resistant IL18 was also effective against MHC class I–deficient tumors via a mechanism that involved enhancing natural killer–cell maturation and polyfunctionality. Collectively, this work identifies IL18BP as a barrier to treatment with IL18 and shows that, if this barrier is overcome, IL18-based therapies may hold promise for treating various malignancies.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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