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  2. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells

CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells

  • Oncoimmunology. 2013 Dec 1;2(12):e26968. doi: 10.4161/onci.26968.
Debbie C Strachan 1 Brian Ruffell 2 Yoko Oei 1 Mina J Bissell 3 Lisa M Coussens 2 Nancy Pryer 1 Dylan Daniel 1
Affiliations

Affiliations

  • 1 Novartis Institutes for Biomedical Research; Emeryville, CA USA.
  • 2 Department of Cell and Developmental Biology and Knight Cancer Institute; Oregon Health and Science University; Portland, OR USA.
  • 3 Life Sciences Division; Lawrence Berkeley National Laboratory; Berkeley, CA USA.
Abstract

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.

Keywords

CSF1R; M-CSF; breast cancer; cervical cancer; transgenic mouse models; tumor immune evasion; tumor immunology; tumor-associated macrophages.

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