Paper

Chemotherapy Induces an IL1β-dependent Neutrophil Recruitment that Promotes Chemoresistance in Metastatic Ovarian Cancer

Ye, Yujie, Yamanoi, Koji, Wickramasinghe, Jayamanna, Zhang, Nan, Hamada, Kohei, Miyamoto, Taito, Mizuno, Rin, Taki, Mana, Ye, Ying, Murphy, Brennah, Minakuchi, Moeko, Manning, Bryan, Murakami, Ryusuke, Nefedova, Yulia, Mandai, Masaki, Kossenkov, Andrew

2025

Overview

High-grade serous carcinoma (HGSC) of the ovary acquires chemoresistance through diverse cancer cell-intrinsic and-extrinsic mechanisms, culminating in treatment-refractory intraperitoneal metastasis. How chemotherapy-induced remodeling of the tumor microenvironment modulates drug sensitivity remains unclear. In this study, we demonstrate that chemotherapy induced IL1β-dependent neutrophil accumulation in tumors, driving chemoresistance in HGSC. Using patient samples, bulk transcriptomic profiling before and after chemotherapy revealed post-treatment upregulation of IL1B, and single-cell RNA sequencing identified myeloid cells as its principal source. In a chemoresistant murine metastatic ovarian cancer model, chemotherapy increased neutrophils and neutrophil extracellular traps (NETs) in omentum tumors; these increases were abrogated in IL1β-deficient mice, with expansion of activated CD8+ T cells and tumor control. Neutrophil depletion in wild-type mice recapitulated the chemosensitive phenotype of IL1β-deficient mice. In vitro, IL1β did not alter cancer cell-intrinsic chemosensitivity, whereas NETs reduced the chemosensitivity of cancer cells. Additionally, the dominant IL1β receptor (IL1R1) was predominantly expressed in tumor-associated fibroblasts in humans and mice. Consistently, IL1R1-deficient mice exhibited chemosensitivity with decreased neutrophil accumulation and increased IFNγ⁺TNF⁺CD8⁺ T cells. We also found that chemotherapy upregulated CXCL2 in patients and that ablating IL1β-IL1R1 axis decreased CXCL2 expression in tumor-associated fibroblasts in mice. Finally, residual human HGSC tumor after chemotherapy showed increased neutrophils and a trend toward more NETs. Collectively, these findings illuminate a paradoxical, cancer cell-extrinsic mechanism in HGSC whereby chemotherapy itself amplifies chemoresistance and suggest that targeting chemotherapy-induced inflammation may help overcome treatment resistance.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Immunology