Journal
ONCOIMMUNOLOGY
Volume 2, Issue 12, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/onci.26968
Keywords
breast cancer; cervical cancer; CSF1R; M-CSF; tumor-associated macrophages; tumor immune evasion; tumor immunology; transgenic mouse models
Categories
Funding
- Department of Defense Breast Cancer Research Program (BCRP)
- NIH/NCI [R01 CA130980, R01CA140943, R01 CA155331, U54 CA163123]
- Department of Defense BCRP Era of Hope Scholar Expansion Award [BC10412]
- Susan G Komen Foundation [KG111084, KG110560]
- Breast Cancer Research Foundation
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Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma. The blockade of CSF1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. However, additional mechanistic insights are needed in order to understand how macrophages are depleted and the global effects of CSF1R inhibition on other tumor-infiltrating immune cells. Using BLZ945, a highly selective small molecule inhibitor of CSF1R, we show that CSF1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8(+) T cells that infiltrate cervical and breast carcinomas. Specifically, we find that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, we show that BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Our results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.
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