Tartrate-Resistant Acid Phosphatase (Tracp) Dependent Polarization Of Breast Cancer-Promoting Macrophages

Background: Breast cancer associated macrophages often promote tumor growth and metastasis by conditioning the tumor microenvironment and suppressing adaptive immune responses. Tartrate-resistant acid phosphatase (TRACP) is a novel serum biomarker associated with systemic macrophage burden in a variety of chronic inflammatory diseases and is strongly expressed by tumor-associated macrophages. We tested the hypothesis that TRACP is required for M2 macrophage polarization. Methods: Macrophage cell lines were polarized in vitro and tested for TRACP, iNOS and Arg-1 expression and their ability to promote or repress breast cancer cell growth and invasion in vitro and in vivo. A novel TRACP deficient, Acp5 mutant mouse was used as a macrophage source and as a breast cancer host to confirm a role for TRACP for macrophages to support cancer growth. Results: TRACP was up-regulated in concert with M2 polarization and down-regulated in M1 polarized cells. TRACP expression correlated with macrophage promotion of tumor growth and invasion in vitro. Although TRACP-deficient macrophages could be induced to express Arg-1 when stimulated with IL-4 plus IL-13 (M2 phenotype), the TRACP deficient macrophages behaved like M1 cells suppressing tumor growth and invasion compared to than WT cells. Tumor xenografts grew slower in primary subcutaneous grafts and metastasized less extensively in intravenous grafts in TRACP deficient mice compared to WT. Furthermore, the tumor metastatic patterns could be reversed in WT animals by co-grafting TRACP-deficient macrophages and in TRACP deficient hosts by co-grafting WT macrophages. Conclusions: TRACP expression is normally a phenotypic marker for alternatively activated macrophages, but not necessary for expression of Arg-1. In a host environment of TRACP deficiency, Arg-1 positive macrophages can be generated by cytokine stimulation in vitro and by tumor in vivo, however, TRACP deficiency still conveyed a tumor suppressive phenotype in cell based studies and in intact animals. TRACP plays a role in functional polarization of M2 macrophages and their ability to promote breast cancer growth and metastasis. Citation Format: Dai M-S, Janckila A, Lo H-C, Wu C-C, Chao T-Y, Yu J-C. Tartrate-resistant acid phosphatase (TRAcP) dependent polarization of breast cancer-promoting macrophages. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-08.