Inhibition of class IIa HDACs with TMP195 promotes a macrophage-dependent reduction in tumor burden.
Major finding: Inhibition of class IIa HDACs with TMP195 promotes a macrophage-dependent reduction in tumor burden.
Approach: TMP195 alters the tumor microenvironment to promote antitumor macrophage recruitment and differentiation.
Impact: Targeting class IIa HDACs may enhance the efficacy of chemotherapy and checkpoint blockade.
Tumor-associated macrophages (TAM) are often protumorigenic, and strategies have emerged to promote their antitumor effects. Selective inhibition of class IIa histone deacetylases (HDAC) with the small-molecule inhibitor TMP195 induces changes in monocyte gene expression without affecting lymphocyte gene expression, and promotes a type 1 proinflammatory monocyte phenotype. Thus, Guerriero and colleagues tested the hypothesis that class IIa HDAC inhibition promotes an antitumor innate immune response using a transgenic mouse model of luminal B-type mammary carcinoma in which CSF-1 and macrophages control late-stage carcinogenesis and pulmonary metastasis. Indeed, TMP195 induced a macrophage-dependent decrease in tumor burden and pulmonary metastasis. TMP195 promoted expression of genes associated with an activated immune cell signature, increased the proportion of CD11b+ cells and mature macrophages, reduced the proportion of protumor TAMs, induced the appearance of cells resembling highly phagocytic tingible body macrophages, and increased the proportion of activated cytotoxic (granzyme B positive) T lymphocytes in tumors. Altogether, these findings suggest that class II HDAC inhibition enhances the phagocytic and immunostimulatory functions of macrophages, promoting an antitumor phenotype that boosts activation of cytotoxic T lymphocytes. In vivo, depletion of myeloid cells or macrophages reduced the antitumor activity of TMP195, indicating that activated macrophages are required for TMP195-mediated tumor suppression. Further, IFNγ was required to alter the tumor microenvironment and activate the TMP195-mediated antitumor immune response. In the mouse model of breast cancer, TMP195 enhanced the efficacy and durability of chemotherapy and anti-PD1 immunotherapy. Collectively, these findings demonstrate that inhibition of class IIa HDACs can promote tumor suppression by enhancing the antitumor activity of macrophages, and suggest that targeting class IIa HDACs may potentially enhance the efficacy of standard therapies in patients with breast cancer.
Guerriero JL, Sotayo A, Ponichtera HE, Castrillon JA, Pourzia AL, Schad S, et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 2017;543:428–32.
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