Journal Article

Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages

Castrillon, Jessica A., Nolan, Michael A., Guerriero, Jennifer L., Sotayo, Alaba, Carrasco, Ruben D., Lazo, Suzan, Lobera, Mercedes, Bronson, Roderick T., Johnson, Shawn F., Ponichtera, Holly E., Schad, Sara, Pourzia, Alexandra L., Letai, Anthony, Davis, Scott P.

2017

Overview

A selective class IIa histone deacetylase inhibitor induces anti-tumour immunity in a mouse model of mammary cancer through altered differentiation and recruitment of tumour-associated macrophages. Using anti-tumour macrophages in breast cancer Tumour-associated macrophages often benefit tumours, but previous efforts to either deplete or stimulate them have had some anti-tumour effects. Anthony Letai and colleagues suggest that using drugs to modify their phenotype could be even more successful. They show that a class IIa histone deacetylase inhibitor, TMP195, induces anti-tumour immunity in a mouse model of breast cancer. Treatment is associated with altered differentiation and recruitment of tumour-associated macrophages, and acts synergistically with chemotherapy and T-cell checkpoint blockade. Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects 1 , but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) 2 , 3 or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) 4 , 5 tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro 6 . Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/2 / 13/21 / 13/31 / 13/51 / 14/19 / 14/34 / 14/63 / 38/39 / 631/250/2504/342 / 631/67/1347 / 631/67/580 / 64/60 / 82/80 / Animals / Benzamides - pharmacology / Benzamides - therapeutic use / Breast cancer / Breast Neoplasms - blood supply / Breast Neoplasms - drug therapy / Breast Neoplasms - enzymology / Breast Neoplasms - immunology / Breast tumors / Cancer metastasis / Cancer therapies / Cell Differentiation - drug effects / Cell Line, Tumor / Disease Models, Animal / Drug Synergism / Female / Gene expression / Health aspects / Histone Deacetylase Inhibitors - classification / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylase Inhibitors - therapeutic use / Humanities and Social Sciences / Humans / Immune system / Inhibitor drugs / letter / Leukocytes / Lung Neoplasms - drug therapy / Lung Neoplasms - immunology / Lung Neoplasms - secondary / Macrophage Activation - drug effects / Macrophages / Macrophages - cytology / Macrophages - drug effects / Macrophages - immunology / Metastasis / Mice / multidisciplinary / Oxadiazoles - pharmacology / Oxadiazoles - therapeutic use / Phagocytosis - drug effects / Prevention / Science / Tumor Burden - drug effects / Tumor Burden - immunology / Tumors