IL25+ macrophages are a key determinant of treatment resistance of IL17RB+ breast cancer.

Recurrence and metastasis are resistant to multimodal treatments, and are the major causes of death in breast cancer. Accumulating evidence suggests that the IL17RB signaling pathway plays a key role in progression and metastasis of breast cancer. Clinical significance of the IL17RB positivity in tumor tissues has been also reported as a poor prognostic factor in breast cancer. However, the molecular mechanisms underlying the poor prognosis of patients with IL17RB+ breast cancer, particularly the immunological aspects, remain to be fully elucidated, and elimination of the IL17RB+ tumors has not been practically achieved in clinical settings. In this study, we identified a distinct molecular mechanism underlying the intractability of the IL17RB+ tumors through tumor biological and immunological investigation using mouse and human breast cancer cells transduced with il17rb gene. IL17RB overexpression in tumor cells confers cancer stemness, including high invasive and self-renewal abilities, and high resistance to CDK4/6 inhibitors that have been considered as a promising agent for treating breast cancer despite the limited efficacy. In the mice implanted with the IL17RB+ tumors, IL25+ macrophages (Møs) are expanded locally in tumor tissues and systemically in spleen, and promote the IL17RB+ tumor progression directly by intensifying the tumor functions, and indirectly via impairment of anti-tumor effector CTLs and NK cells utilizing the secreted IL25. Blocking IL25 with the specific mAb, however, interferes the adverse events, and successfully elicits significant anti-tumor efficacy in combination with CDK4/6 inhibitors providing better survival in murine mammary tumor models. These results suggest that the IL25+ Mø is a key determinant of building the solid treatment resistance of the IL17RB+ breast cancer. Targeting the IL17RB-IL25 axis may be a promising strategy to improve clinical outcomes in the treatment of breast cancer patients, particularly with IL17RB+ tumors.