Recurrence and treatment resistance are major causes of cancer-associated death. There has been a growing interest in better understanding epithelial-mesenchymal transition, stemness of cancer cells, and exhaustion and dysfunction of the immune system for which numerous genomic, proteomic, microenvironmental, and immunologic mechanisms have been demonstrated. However, practical treatments for such patients have not yet been established. Here we identified IL33 as a key driver of polyploidy, followed by rapid proliferation after treatment. IL33 induction transformed tumor cells into polyploid giant cells, showing abnormal cell cycle without cell division accompanied by Snail deregulation and p53 inactivation; small progeny cells were generated in response to treatment stress. Simultaneously, soluble IL33 was released from tumor cells, leading to expansion of receptor ST2-expressing cells including IL17RB+GATA3+ cells, which promoted tumor progression and metastasis directly and indirectly via induction of immune exhaustion and dysfunction. Blocking IL33 with a specific mAb in murine IL33+ metastatic tumor models abrogated negative consequences and successfully elicited antitumor efficacy induced by other combined treatments. Ex vivo assays using tumor tissues and peripheral blood mononuclear cells of patients with cancer validated the clinical relevancy of these findings. Together, these data suggest that targeting the IL33-ST2 axis is a promising strategy for diagnosis and treatment of patients likely to be resistant to treatments in the clinical settings. SIGNIFICANCE: These findings indicate that the functional role of IL33 in cancer polyploidy contributes to intrinsic and extrinsic mechanisms underlying treatment failure.
©2020 American Association for Cancer Research.