title: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Guerriero
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Alaba
authors.initials: A
authors.lastname: Sotayo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Ponichtera
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Castrillon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Pourzia
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Schad
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Shawn F
authors.initials: SF
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Massachusetts 02115, USA.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Carrasco
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Suzan
authors.initials: S
authors.lastname: Lazo
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: GlaxoSmithKline, 200 Technology Square Suite 602, Cambridge, Massachusetts 02139, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Davis
authors.affiliation: GlaxoSmithKline, 200 Technology Square Suite 602, Cambridge, Massachusetts 02139, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lobera
authors.affiliation: GlaxoSmithKline, 200 Technology Square Suite 602, Cambridge, Massachusetts 02139, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nolan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000145:classification* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D010587:Phagocytosis / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D010069:Oxadiazoles; C000621948:TMP195