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

Nature volume 543, pages 428432 (16 March 2017) | Download Citation


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 effects1, 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 vitro6. 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.

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We thank A. Benowitz and C. Leach for their support and discussions in the preparation of the manuscript. This work was supported by NIH NCI F32CA180733 (J.L.G.), The Friends of Dana-Farber, Dancing for a Cure (J.L.G.), NIH NCI R01CA205967 (A.L.) and a sponsored research agreement from GlaxoSmithKline (A.L., J.L.G.).

Author information

Author notes

    • Michael A. Nolan
    •  & Anthony Letai

    These authors jointly supervised this work.


  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02115, USA

    • Jennifer L. Guerriero
    • , Alaba Sotayo
    • , Holly E. Ponichtera
    • , Jessica A. Castrillon
    • , Alexandra L. Pourzia
    • , Sara Schad
    • , Shawn F. Johnson
    • , Suzan Lazo
    •  & Anthony Letai
  2. Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Massachusetts 02115, USA

    • Ruben D. Carrasco
  3. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Roderick T. Bronson
  4. GlaxoSmithKline, 200 Technology Square Suite 602, Cambridge, Massachusetts 02139, USA

    • Scott P. Davis
    • , Mercedes Lobera
    •  & Michael A. Nolan


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J.L.G., M.A.N. and A.L. conceived the project and designed the experiments. J.L.G., A.S., H.E.P., A.L.P., S.S., S.F.J., J.A.C. and M.A.N. performed the biological experiments and analysed the data. R.T.B. and R.D.C. performed histopathological analysis. S.L. assisted flow cytometry analysis. S.P.D. assisted with statistical analysis of gene expression arrays. J.L.G., S.P.D. and M.A.N. prepared figures and tables. J.L.G., M.A.N. and A.L. wrote and edited the manuscript with help from co-authors. J.L.G., M.L., M.A.N. and A.L. contributed to oversight of and advice on the overall project. J.L.G., M.A.N and A.L. provided overall project leadership.

Competing interests

This work was supported though a sponsored research agreement with GlaxoSmithKline to A.L. and J.L.G. S.P.D., M.L. and M.A.N. are GlaxoSmithKline employees.

Corresponding authors

Correspondence to Michael A. Nolan or Anthony Letai.

Reviewer Information Nature thanks B. Ruffell and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Figure 1

    This file contains the source data gels for Extended Data Figure 5.

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