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

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 fibroblasts in humans and mice.

Consistently, IL1R1-deficient mice exhibited chemosensitivity with decreased neutrophil accumulation and increased IFNγ⁺CD8⁺ T cells. We also found that chemotherapy upregulated CXCL2 in patients and that ablating IL1β-IL1R1 axis decreased CXCL2 expression in fibroblasts in mice. Finally, residual human HGSC tumor after chemotherapy showed increased neutrophils and a trend toward more NETs.

Collectively, these findings illuminate one facet of cancer-extrinsic mechanisms of chemoresistance in HGSC and suggest that targeting therapy-induced inflammation may help overcome treatment resistance.