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J Immunother Cancer. 2014 Apr 15;2:8. doi: 10.1186/2051-1426-2-8. eCollection 2014.

The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells.

Author information

1
Department of Molecular and Medical Pharmacology, 650 Charles E. Young Drive South, 23-120 Center for Health Sciences, Los Angeles, CA 90095-1735, USA.
2
Department of Neurosurgery, University of California-Los Angeles School of Medicine, Center for Health Sciences, Room 74-145 CHS, 10833 Le Conte Avenue, Box 956901, Los Angeles, CA 90095-6901, USA.
3
Department of Neurosurgery, University of California-Los Angeles School of Medicine, Center for Health Sciences, Room 74-145 CHS, 10833 Le Conte Avenue, Box 956901, Los Angeles, CA 90095-6901, USA ; Jonsson Comprehensive Cancer Center, University of California-Los Angeles School of Medicine, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781, USA.
4
Department of Neurosurgery, University of California-Los Angeles School of Medicine, Center for Health Sciences, Room 74-145 CHS, 10833 Le Conte Avenue, Box 956901, Los Angeles, CA 90095-6901, USA ; Jonsson Comprehensive Cancer Center, University of California-Los Angeles School of Medicine, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781, USA ; Brain Research Institute, University of California-Los Angeles School of Medicine, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
5
Department of Molecular and Medical Pharmacology, 650 Charles E. Young Drive South, 23-120 Center for Health Sciences, Los Angeles, CA 90095-1735, USA ; Department of Neurosurgery, University of California-Los Angeles School of Medicine, Center for Health Sciences, Room 74-145 CHS, 10833 Le Conte Avenue, Box 956901, Los Angeles, CA 90095-6901, USA ; Jonsson Comprehensive Cancer Center, University of California-Los Angeles School of Medicine, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095-1781, USA ; Brain Research Institute, University of California-Los Angeles School of Medicine, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.

Abstract

BACKGROUND:

Histone deacetylase (HDAC) inhibitors are a class of agents that have potent antitumor activity with a reported ability to upregulate MHC and costimulatory molecule expression. We hypothesized that epigenetic pharmacological immunomodulation could sensitize tumors to immune mediated cell death with an adoptive T cell therapy.

METHODS:

The pan-HDAC inhibitor, LBH589, was combined with gp100 specific T cell immunotherapy in an in vivo B16 melanoma model and in an in vivo non-tumor bearing model. Tumor regression, tumor specific T cell function and phenotype, and serum cytokine levels were evaluated.

RESULTS:

Addition of LBH589 to an adoptive cell transfer therapy significantly decreased tumor burden while sustaining systemic pro-inflammatory levels. Furthermore, LBH589 was able to enhance gp100 specific T cell survival and significantly decrease T regulatory cell populations systemically and intratumorally. Even in the absence of tumor, LBH589 was able to enhance the proliferation, retention, and polyfunctional status of tumor specific T cells, suggesting its effects were T cell specific. In addition, LBH589 induced significantly higher levels of the IL-2 receptor (CD25) and the co-stimulatory molecule OX-40 in T cells.

CONCLUSION:

These results demonstrate that immunomodulation of adoptively transferred T cells by LBH589 provides a novel mechanism to increase in vivo antitumor efficacy of effector CD8 T cells.

KEYWORDS:

Dendritic cells; Inflammation; T cells; Tumor immunity

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