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

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

Citation: Strachan DC, Ruffell B, Oei Y, Bissell M, Coussens LM, Pryer N, Daniel D. 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; 2:e26968; 10.4161/onci.26968

Disclosure of Potential Conflicts of Interest

DCS, at the time of the study, was a Novartis Presidential Postdoctoral Fellow funded by the Novartis Education Office and the Novartis Institutes for Biomedical Research. Authors YO, NP and DD are employees of the Novartis Institutes for Biomedical Research. The funders had no role in study design and implementation, data analysis, and manuscript preparation. There are no patents, products in development or marketed products involved. The authors declare no conflicting interests.

Acknowledgments

The authors would like to thank Cyrus Ghajar and Irene Kuhn for helpful discussions, Nicole Vanasse and Brenda Bartholomew for maintaining the transgenic mice, and Sok Chey, Ruben Flores and Jose Lapitan for their support with animal studies. The authors acknowledge support from the Department of Defense Breast Cancer Research Program (BCRP) to B.R., and grants from the NIH/NCI (R01 CA130980, R01CA140943, R01 CA155331, U54 CA163123), the Department of Defense BCRP Era of Hope Scholar Expansion Award (BC10412), the Susan G Komen Foundation (KG111084, KG110560), and the Breast Cancer Research Foundation to LMC.