Abstract PR007: IL1β+ myeloid cells fuel/induce neutrophil-driven chemoresistance in metastatic ovarian cancer

Abstract High-grade serous ovarian carcinoma (HGSOC) is typically treated with chemotherapy followed by surgery, but most patients relapse with drug-resistant disease. To improve clinical outcomes, there is an urgent need for novel therapies that can effectively target chemo-resistant ovarian cancer (OC) metastases. We found that IL1β was upregulated in chemo-treated human HGSOC metastases samples compared to pre-treatment samples using published datasets. We also observed that higher IL1β correlated with poorer survival rates in chemo-treated HGSOC patients. These findings led us to hypothesize that IL1β contributes to chemo-resistant HGSOC metastases. To test our hypothesis, I used a chemo-resistant murine ovarian cancer (OC) cell line, KPCA, and IL1β KO mice to study OC metastases in response to paclitaxel and carboplatin. Tumor metastases were assessed via IVIS bioluminescent imaging, omentum tumor weight, and mesenteric tumor nodules counts. We also evaluated the immune cell landscape inside tumor using flowcytometry. Our results showed that the omentum tumor burden, the number of tumor nodules at the mesentery, and IVIS signals were all decreased in IL1β KO groups in response to paclitaxel and carboplatin compared to controls. Our flow results also showed a significant reduction in infiltrating neutrophils in IL1β KO mice. To explore the underlying mechanism, we conducted a single cell RNA sequencing. Our results showed that an increased frequency of functional T cells including IFNγ+ CD8 T, GZMA+ CD8 T, GZMB+ CD8 T, Perforin+ CD8 T, and TNFα+ CD4 T in chemo-treated KPCA tumors in IL1β KO mice. We also further tested these findings in IL1R1KO mice since IL1R1 is the receptor for IL1β. Consistently, we observed a decrease in tumor burden in IL1R1 KO mice as well as decreased neutrophil infiltration and increased of IFNγ+ CD8 T and Perforin+ CD4 T. To this end, we sought to investigate how IL1β recruits infiltrating neutrophils. We analyzed published bulk RNA sequencing datasets and post-chemotherapy human HGSOC samples and found CXCL2 to be significantly upregulated among known neutrophil-recruiting chemokines. Together, these results suggest that IL1β facilitates neutrophil infiltration via CXCL2, leading to suppression of anti-tumor immunity and a decrease of functional T cells in the chemo-treated tumor microenvironment. To our knowledge, this is the first study to identify IL1β as a potential therapeutic target to counteract neutrophil-induced immune suppression within HGSOC. Citation Format: Yujie Ye, Brennah Murphy, Bryan Manning, Yulia Nefedova, Andrew Kossenkov, Taito Miyamoto, Nan Zhang. IL1β+ myeloid cells fuel/induce neutrophil-driven chemoresistance in metastatic ovarian cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr PR007.