Tumor macrophages generally promote tumorigenesis and are associated with increased vascular density, resistance to chemotherapy and a worse clinical outcome in the majority of human tumors. Therefore, significant pharmaceutical effort has focused on inhibiting the immunosuppressive effects of tumor macrophages by depleting or inhibiting them. However, macrophage types also exist that can promote tumor clearance. Shifting tumor macrophages to an anti-tumor phenotype offers great hope given their plasticity and high numbers in a variety of solid tumors. We recently reported that a novel, first in class, specific class IIa HDAC inhibitor, TMP195, significantly alters the gene expression signature of human monocytes and promotes their polarization to an anti-tumor phenotype in vitro. Here, we demonstrate that a first in class, class IIa histone deacetylase (HDAC) inhibitor, TMP195, can activate tumor macrophages in vivo to induce tumor regression and inhibit pulmonary metastases in a mouse model of breast cancer. We find that TMP195 induces macrophage recruitment and differentiation of highly phagocytic cells within the tumor, which increases tumor cell death while decreasing angiogenesis. Strikingly, we find that TMP195 enhances chemotherapy and immunotherapy to induce durable tumor reduction. These data reveal a novel role for harnessing the anti-tumor potential of macrophages to enhance cancer therapy.

Citation Format: Jennifer L. Guerriero, Alaba Sotayo, Holly E. Ponichtera, Jessica A. Castrillon, Alexandra L. Pourzia, Sara Schad, Shawn F. Johnson, Ruben D. Carrasco, Susan B. Lazo, Roderick T. Bronson, Scott P. Davis, Mercedes X. Lobera, Michael A. Nolan, Anthony Letai. Class IIa HDAC inhibition promotes an antitumor macrophage phenotype that induces breast tumor regression and inhibits metastasis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B35.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.