Dr. Ting Zhou

Cytokine immunotherapy has been a pioneer in demonstrating durable anti-tumor efficacy in patients but was dampened by its pleiotropism and negative feedback. In this work, we identified the decoy receptor of IL-18, IL-18BP, is highly elevated in tumor microenvironment and served as a soluble immune checkpoint and barrier to effective IL-18 immunotherapy. We continued to engineer decoy-resistant IL-18 (DR-18), which maintains receptor signaling ability but bypasses the inhibition of IL-18BP. DR-18 elicits strong anti-tumor efficacy through augmenting effector T cell function and expanding TCF1+ memory precursor CD8+ T cell pool. Our study therefore established the basis of combing synthetic protein engineering with immuno-pharmacology to investigate complex cytokine regulatory pathway and pave the way for the clinic translation.