IL33 Is a Key Driver of Treatment Resistance of Cancer

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 þ GATA3 þ 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 þ 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. Materials and Methods MiceFive-week-old female C57BL/6 mice were purchased from Charles River Laboratories, and were maintained under pathogen-free conditions. The mice were used according to the protocols approved by the Animal Care and Use Committee at the National Cancer Center Research Institute (Tokyo, Japan). Cell linesHuman breast cancer cell lines (MCF7 and MDA-MB-231) were purchased from ATCC, and were authenticated by short tandem repeat profiling. Murine melanoma B16-B10 cells were purchased from the Cell Resource Center for Biomedical Research at Tohoku University in Japan. We used B16-F10 cells transfected with plasmid vector pcDNA3.1(þ) encoding neomycin-resistant gene with or without murine snail (F10-snail þ or F10-mock) that we established before (7). All tumor cells were tested for Mycoplasma negativity using a Hoechst-staining Detection Kit (MP Biomedicals) and were expanded and frozen in liquid nitrogen to avoid changes occurred by a long-term culture until used in experiments. Establishment of B16-F10 subclonesF10-mock cells were harvested from subcutaneous tumors (F10primary) and femur bone marrow (F10-BM) of mice 25 days after implantation and were cultured in 10% FBS/DMEM with Geneticin

Interleukins in cancer: from biology to therapy

“…It was shown in a preclinical study that IL33 may directly act on tumour cells, inducing poly ploidy and rapid proliferation, and causing therapy resis tance. Use of a specific IL33blocking antibody could restore the efficacy of antiPD1 therapy in an otherwise ICIresistant subclone of the B16F10 melanoma model 179 .…”

The Janus Face of IL-33 Signaling in Tumor Development and Immune Escape

“…IL-33 treatment also drove the induction and cytotoxic activities of DC-induced Tc9 cells, a subset of effector CD8 + T cells producing cytotoxic IL-9, and further promoted the therapeutic efficacy of DC-based tumor vaccines [208]. Apart from triggering the IL-33/ST2 signaling to augment cancer immunotherapy, a number of studies showed the blockade of IL-33, ST2, or both resulted in growth inhibition of tumors [120,209,210] in association with reduced accumulation of ST2 + tumor-promoting cells, such as T reg , TAM, and IL17RB + ILC2. Furthermore, combination with ICB revealed a synergistic antitumor effect [210].…”

Interleukin (IL)‐33: an orchestrator of immunity from host defence to tissue homeostasis

“…These cells produce AREG and IL-13, respectively, and therefore forms a protumorigenic microenvironment in the breast, lung, head and neck, and colon. 94,[97][98][99] Taken together, targeting IL-33 remains a therapeutic option for dysfunction and allergic disease. In fact, Clinicaltrials.gov has listed anti-IL-33 clinical trials in patients with asthma, food allergy, chronic rhinosinusitis and chronic obstructive airway disease (accessed 19 February 2020).…”