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Investigation into the role of eosinophils in pulmonary metastasis and primary tumours in mouse models of breast cancer

University of British Columbia

Eosinophils are multifunctional granulocytes with potent immune modulatory and cytotoxic capabilities. Despite the presence of eosinophils in various solid tumours and eosinophilia being a prognosistic indicator in some cancers, the role of this innate immune cell has been largely overlooked in the context of cancer. Specifically, the role of eosinophils in pulmonary metastasis is poorly described despite their prevalence in the lung and association with various pulmonary diseases. I sought to delineate the role of eosinophils in murine models of metastatic breast cancer using novel mouse models of genetic eosinophil deficiency (ddGATA) and by immunodepletion in orthotopic mouse models of cancer using an anti-IL-5 antibody. I hypothesize that eosinophils enhance pulmonary metastasis in mouse models of breast cancer, but do not affect the vascularization of the primary tumour. Eosinophils are increased 5.8-fold in the lungs of mice bearing 4T1 metastatic mammary tumours (p<0.001) which may be due to an observed 4-fold increase in the expression of CCL24 (p<0.0001) that is produced by mMDSCs. Moreover, some resident eosinophils appeared to differentiate into a novel CD11bhiGr-1hi subset in the pre-metastatic lungs. Immunological depletion of eosinophils using anti-IL-5 antibody did not affect the growth or vascularization of 4T1 tumours, or metastatic development by 3 weeks post-implant of the primary tumour. Surprisingly, there was a trend towards an increase in tumour cell colonization of the lungs by IV injected LLC—but not E0771-LMB—tumour cells in ddGATA mice relative to WT controls; indicating that eosinophils may exert anti-tumour effects in this model. Furthermore, IL-5Tg mice exhibiting eosinophilia had a 5-fold decrease in the number of lung Tregs (p<0.001) and were significantly protected from tumour cell colonization of the lungs. Our data suggests that a pro-inflammatory subset of CD11b hiGr-1hi eosinophils may be present in the pre-metastatic lungs and additional eosinophils are recruited to the metastatic lung in response to CCL24 produced by mMDSCs. However, eosinophils do not significantly influence pulmonary metastasis or primary tumour growth or vascularization in mouse models of breast cancer. Furthermore, our data indicates that IL-5 may be exerting pleiotropic effects on other immune cell populations.

Text

2017-07-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62442

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/