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Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma

Leukemia volume 32, pages 843–846 (2018)Cite this article

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Histone deacetylases (HDACs) are attractive therapeutic targets, and selective HDAC inhibitors (HDACi), alone or in combination with other anti-cancer agents, are promising treatment strategies in multiple myeloma (MM).1234To date, however, the effect of HDACi on immune regulation in the MM bone marrow (BM) microenvironment, as well as the therapeutic potential of combining selective HDACi with immune-based therapies, is undefined. Recent studies showed that besides histone modification, HDACs also modulate non-histone targets including immune regulatory molecules.5, 6 For example, blockade of HDACs upregulates immunecheckpoints such as PD-1 ligand (PD-L1).6 Moreover, the combination of HDACi with PD-1/PD-L1 checkpoint blockade significantly improves immunotherapy in a murine B16F10 model.6 In MM, PD-L1 expression directly correlates with progression of disease, with highest levels in patients with relapsed/refractory MM.7, 8 Here, we utilized an orally bioavalable HDAC6 selective inhibitor ACY-241, currently in clinical trials,9 to examine whether the combination of ACY-241 with anti-PD-L1 antibody enhances anti-MM immunity in the MM BM microenvironment.

We first evaluated whether the combination of ACY-241 and anti-PD-L1 Ab enhances MM patient NK cell-mediated cytolytic activity. For these studies, we utilized low concentration of ACY-241 that do not significantly affect the viability of pDCs, T cells or NK cells (Supplementary Figure 1 A-C). Freshly isolated NK cells from MM patient BM (n=7) were co-cultured with autologous pDCs in the presence of anti-PD-L1 Ab (5 μg/ml), ACY-241 (0.2 μM) or ACY-241 plus anti-PD-L1 Ab for 5 days. Cells were washed and resuspended in complete medium without drugs and cultured with autologous MM cells prestained with Celltrace violet for 24 h, followed by 7-AAD staining and quantification of MM cell lysis by flow cytometry. The combination of ACY-241 and anti-PD-L1 Ab triggered a more robust NK cell-mediated cytotlytic activity against MM cells than either agent alone (Figure 1b and c). No significant NK cell-mediated cytotoxicity was noted in the absence of pDCs in these experiments (Supplementary Figure 2B), confirming a key role of pDCs in NK cell functioning in response to treatment with ACY-241 and/or anti-PD-L1 Ab. To further confirm our findings, we next performed analysis of CD107a as a marker of NK cell function. MM patient pDCs and autologous NK cells were treated with ACY-241, anti-PD-L1 Ab or ACY-241 plus anti-PD-L1 Ab, followed by degranulation assay to assess surface CD107a expressing CD3−/CD56+ NK cells by multi-parameter flow cytometry. In concert with our finding shown in Figures 1b and c, ACY-241 plus anti-PD-L1 Ab increases CD107a+ degranulated cytolytic NK cells (Supplementary Figure 3).

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Acknowledgements

This investigation was supported by National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant P50100707, RO1 CA207237 (DC and KCA) and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor.

Author contributions

AR performed the experiments, designed research, analyzed data and wrote the manuscript; YS, TH, DSD helped in flow cytometry; DC designed research, analyzed data and wrote the manuscript; and KCA analyzed data and wrote the manuscript.

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  1. D Chauhan and K C Anderson: DC and KCA are Joint Senior authors.

Authors and Affiliations

  1. Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A Ray, D S Das, Y Song, T Hideshima, Y-T Tai, D Chauhan & K C Anderson

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  1. A Ray
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  2. D S Das
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Correspondence to D Chauhan or K C Anderson.

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Competing interests

KCA is an advisor for Celgene, Millennium Pharmaceuticals and Gilead Sciences, and is a Scientific Founder of OncoPep and C4 therapeutics. Other authors have no competing financial interests.

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Ray, A., Das, D., Song, Y. et al. Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32, 843–846 (2018). https://doi.org/10.1038/leu.2017.322

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