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

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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.

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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

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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.

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  1. Mirati Therapeutics, Inc., 9393 Towne Center Dr, Suite 200, San Diego, CA, 92121, USA

    David Briere, Niranjan Sudhakar, Jill Hallin, Lars D. Engstrom, Ruth Aranda, Harrah Chiang, Peter Olson & James G. Christensen

  2. NYU Langone Medical Center, New York, NY, 10016, USA

    David M. Woods, Andressa L. Sodré & Jeffrey S. Weber

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  1. David Briere
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Correspondence to James G. Christensen.

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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.

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Briere, D., Sudhakar, N., Woods, D.M. et al. The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy. Cancer Immunol Immunother 67, 381–392 (2018). https://doi.org/10.1007/s00262-017-2091-y

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