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

Abstract

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, 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) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) 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. 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.

Repolarizing macrophages improves breast cancer therapy

“…In the paper by Guerriero et al [8] a new approach to reprogram monocytes and macrophages into tumoricidal cells is described using TMP195, a new Class IIa Histone Acetyl Deacetylase (HDAC) inhibitors. HDACs are part of the enzymatic machinery that modifies chromatin [9] by histone de-acetylation thus changing the cell's transcriptional profile.…”

Harnessing class II histone deacetylases in macrophages to combat breast cancer

“…3 An alternative approach to replace macrophage depletion strategies could be based on the fact that tumor-associated macrophages preserve their plasticity, which provides therapeutic potential to re-program them from tumor-promoting cells to cells with tumoricidal activities. In a recent study, Guerriero et al 4 provided further data supporting the notion that rendering tumor-associated macrophages to display anti-tumorigenic activities may be beneficial. Until recently, the therapeutic potential of class IIa histone deacetylases (HDAC) (for example, HDAC4, HDAC5, HDAC7 and HDAC9) was impaired by the lack of potent and selective compounds that can antagonize their function.…”

“…These results provided the rationale to test the hypothesis that class IIa HDAC inhibition will promote an anti-tumor innate immune response. To this end, Guerriero et al 4 used TMP195 in vivo using a macrophage-dependent mouse model, namely, the MMTV-PyMT mammary carcinoma. 6 Tumor-bearing mice treated with TMP195 displayed increased levels of CD11b+ myeloid cells, specifically in macrophages.…”

Insights into the Link Between Obesity and Cancer

“…It has also been shown that a class IIa histone deacetylase (HDAC) inhibitor, TMP195, can stimulate macrophages to have an anti-tumor phenotype. This inhibitor reduces tumor burden and pulmonary metastases in a macrophage-dependent mouse model of breast cancer [65].…”