Breast carcinoma is the most frequent malignant tumor of women in western countries with nearly 1 in 8 being affected. Tumor associated macrophages (TAM) are the primary immune cell type present in nearly all solid tumors including breast tumors. Currently, it is proposed that TAMs originate from Hematopoietic stem cells (HSC) and generate an immunosuppressive niche by interacting with other immune cells to facilitate tumor progression and metastasis. Therapeutic removal of TAMs for example by antibodies or small molecule inhibitors against the receptor for macrophage colony stimulating factor 1 (Csf1r) slows or prevents the progression of tumors in various animal models and clinical trials indicating that TAMs are a potential target for cancer treatment. However, recent studies on mammary and pancreatic cancer in mice defective in recruiting HSC-derived TAMs into tumors suggest that these cells are not the only macrophage subset contributing to tumor growth. Emerging evidence from our lab and others indicate that in addition to HSC-derived myeloid cells, there exists a separate myeloid lineage that originates from yolk sac erythro-myeloid progenitors (EMPs). These yolk sac derived myeloid cells are tissue resident and colonize tissue anlagen at onset of organogenesis to promote organ growth and tissue health via direct removal of unwanted/unfit cells and secretion of growth factors. For example, brain tissue resident microglia phagocytose unfit neurons and secrete neurotropic growth factors. The role of tissue resident macrophages in tumor growth is not known. We hypothesize that tissue resident macrophages directly interact with tumors at early stages of tumorigenesis to remove pre-cancerous/unfit cells; however, later in tumorigenesis they promote growth via secretion of growth factors or acquisition of somatic mutations that promote an immunosuppressive niche. In this project, we propose to (Aim 1) characterize macrophage heterogeneity within normal and tumor-bearing mammary glands in mice and humans and to (Aim 2) investigate for the first time the function of tissue resident macrophages in mammary tumor development.
The dominant immune cells in all solid tumors are macrophages. Removal of macrophages improves cancer prognosis and reduces tumor growth. However, macrophages are developmentally heterogeneous, some arise from the bone marrow while others develop during embryogenesis. Here, we will characterize different macrophage populations in tumors to identify their functions and develop better and more targeted cancer therapies as some macrophages may aid tumor growth while other may inhibit it.
