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Cancer Immunology, Immunotherapy

, Volume 67, Issue 3, pp 381–392 | Cite as

The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy

  • David Briere
  • Niranjan Sudhakar
  • David M. Woods
  • Jill Hallin
  • Lars D. Engstrom
  • Ruth Aranda
  • Harrah Chiang
  • Andressa L. Sodré
  • Peter Olson
  • Jeffrey S. Weber
  • James G. ChristensenEmail author
Original Article

Abstract

Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon γ (IFN-γ) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy.

Keywords

Immunotherapy Histone deacetylase T regulatory cells Chromatin immunoprecipitation Epigenetics 

Abbreviations

CIITA

Class II transactivator

Ccl5

Chemokine (C–C motif) ligand 5

CDKN1A

Cyclin-dependent kinase inhibitor 1A

CDR3

Complementarity determining region 3

ChIP-Seq

Chromatin immunoprecipitation-sequencing

Cxcr6

Chemokine (C–X–C motif) receptor 6

FOS

FBJ murine osteosarcoma viral oncogene homolog

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

GUSB

Glucuronidase, beta

H2-Aa

Histocompatibility 2, class II antigen A, alpha

H3K4me3

Histone 3 lysine 4 trimethylation

H3K27Ac

Histone 3 lysine 27 acetylation

HDAC

Histone deacetylase

HLA

Human leukocyte antigen

IFN-γ

Interferon γ

Iso Ab

Isotype antibody

MDSC

Myeloid-derived suppressor cell

MHC

Major histocompatibility

MIC-A/B

MHC class I polypeptide-related sequence A/B

NSCLC

Non-small cell lung cancer

RT

Reverse transcription

SEM

Standard error of the mean

TCR

T-cell receptor

Treg

T-regulatory cell

Notes

Acknowledgements

We thank Molecular Imaging (Ann Arbor, MI) for conducting the in vivo and flow cytometry studies. We thank Active Motif (Carlsbad, CA) for assistance designing and for running ChIP-Seq studies. We thank Diane Potvin, Head of Biostatistics and Data Management and Consultant to Mirati Therapeutics for statistical analyses. We thank Dana Buckman, Flow Paradigm (San Diego, CA), for flow cytometry support. We thank Adaptive Biotechnologies (Seattle, WA) for tumor TCR sequencing and bioinformatics analyses.

Compliance with ethical standards

Conflict of interest

David Briere, Niranjan Sudhakar, Jill Hallin, Lars D. Engstrom, Ruth Aranda, Harrah Chiang, Peter Olson, James G. Christensen are employees and stockholders of Mirati Therapeutics. Jeffrey S. Weber, David M. Woods and Andressa L. Sodré received research funding from Mirati Therapeutics.

Supplementary material

262_2017_2091_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1109 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • David Briere
    • 1
  • Niranjan Sudhakar
    • 1
  • David M. Woods
    • 2
  • Jill Hallin
    • 1
  • Lars D. Engstrom
    • 1
  • Ruth Aranda
    • 1
  • Harrah Chiang
    • 1
  • Andressa L. Sodré
    • 2
  • Peter Olson
    • 1
  • Jeffrey S. Weber
    • 2
  • James G. Christensen
    • 1
    Email author
  1. 1.Mirati Therapeutics, Inc.San DiegoUSA
  2. 2.NYU Langone Medical CenterNew YorkUSA

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