IL33 Is a Key Driver of Treatment Resistance of Cancer

Cancer Research
Chie Kudo-SaitoNarikazu Boku

Abstract

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 ...Continue Reading

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Citations

Jul 29, 2020·Frontiers in Immunology·Moritz F EissmannMatthias Ernst
Jun 23, 2020·Clinical & Translational Immunology·Zekun ZhouOusheng Liu
Dec 29, 2020·Frontiers in Oncology·Daniel Peña-OyarzúnAlfredo Criollo
Feb 5, 2021·Cancers·Chie Kudo-SaitoYamato Ogiwara
Apr 12, 2021·Seminars in Cancer Biology·Jing ZhangXinzhe Liu
Jun 5, 2021·Nature Reviews. Cancer·Daria BriukhovetskaSebastian Kobold
Jun 17, 2021·European Journal of Immunology·Wenyi JiangYi Zhang
Sep 30, 2021·Molecular Medicine·Paola AllavenaCristina Belgiovine

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