We have demonstrated that targeting Tumour Associated Macrophages (TAMs) via their growth factor Colony Stimulating Factor-1 (CSF-1) unexpectedly increased metastasis to lung and bone in two mouse models of breast cancer, accompanied by an increase in circulating and Tumour Associated Neutrophils (TANs) and an increase in plasma levels of the neutrophil growth factor Granulocyte Colony Stimulating Factor (G-CSF). Targeting the G-CSF receptor (G-CSFR) overcame this increase in metastasis and neutrophil accumulation. This project now aims to characterize the role of neutrophils and G-CSF signalling in enhancing breast cancer metastasis, and to identify appropriate chemotherapy regimes suitable for combination with G-CSFR antibody treatment potentially for patients.
Syngeneic mouse models of breast cancer were established by 4T1.2 tumour cell injection into the mammary gland and mice were treated alone or in combination with cytotoxic chemotherapy and G-CSFR antibody. Treatment efficacy was assessed by flow cytometry for changes in immune populations in blood, tumours and lungs. Therapeutic benefit was assessed by survival and level of metastatic burden in lung.
Low dose Doxorubicin alone depletes myeloid (CD11b+) cell populations, including neutrophils, that suppress T-cell activity in the 4T1.2 model, resulting in enhanced anti-tumour responses. However, combination with G-CSFR antibody treatment had little therapeutic benefit. The exact mechanism of action by which G-CSFR antibody alone reduces metastasis is still being characterised. In conclusion, G-CSFR antibody treatment may benefit more from combination with radiotherapy or chemotherapy that directly stimulates T-cell infiltration/activity, rather than therapies also affecting neutrophils themselves.