LAUSR

Malignant tumor progression and aggressive tumor recurrence after treatment are driven by subsets of cancer stem cells (CSCs), but targeting CSCs remains a major challenge due to their plasticity. CSCs in squamous cell carcinoma reside at the tumor-stromal interface, a paramount tumor microenvironment (TME) for interactive crosstalk between cancer cells and various other cells via soluble mediators, and tumor-infiltrating immune cells are pivotal regulators of tumor progression. However, the molecular link between tumor-associated immune-inflammatory responses and the regulation of CSCs are largely unknown. To define a framework of the CSC niche, we have been focusing on crosstalk between TGF-beta-activated CSCs and their neighboring immune cells. By transcriptomic analysis, we identify interleukin-33 (IL-33) as the most upregulated cytokine in TGF-beta-activated CSCs. We find that IL-33 is secreted in response to the activation of antioxidant responses, and IL-33 mobilizes a subset of tumor-promoting macrophages that express the IL-33 receptor in the adjacent stroma. Tumor-specific IL33 knockdown in vivo dampens both invasive carcinogenesis and paracrine TGF-beta signaling in tumor cells, indicating that IL-33 has a crucial role in the formation of TGF-beta-rich tumor-promoting TME by affecting tumor-infiltrating bone marrow-derived monocytes. Together, these findings on a bidirectional paracrine signaling axis provide novel insights into mechanisms of the formation a CSC privilege niche, which may hold great potential to drastically improve the therapeutic efficacy of current and future cancer treatments. Note: This abstract was not presented at the meeting. Citation Format: Naoki Oshimori, Sachiko Oshimori, Ajit Elhance, Justin Leitenberger, Sushil Kumar. Bidirectional paracrine IL-33-TGF-beta signaling underlies a tumor-promoting stem cell niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2033.