Open Access

Journal for ImmunoTherapy of Cancer

, volume 11 , issue 11 , pages e007495

Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy

Christina Kober ^{1, 2, 3, 4}

Julian Roewe ^{5, 6, 7, 8}

Norbert Schmees ^{1, 2}

Lars Roese ^{1, 2}

Ulrike Roehn ^{1, 2}

Benjamin Bader ^{1, 2}

Detlef Stoeckigt ^{1, 2}

Florian Prinz ^{1, 2}

Mátyás Gorjánácz ^{1, 2}

Helge Gottfried Roider ^{1, 2}

Catherine Olesch ^{1, 2, 3, 4}

Gabriele Leder ^{1, 2}

Horst Irlbacher ^{1, 2}

Ralf Lesche ^{1, 2}

Julien Lefranc ^{1, 2}

Mine Oezcan-Wahlbrink ^{1, 2, 3, 4}

Ankita Sati Batra ^{5, 6, 7, 8}

Nirmeen Elmadany ^{5, 6, 7, 8}

Rafael Carretero ^{1, 2, 3, 4}

Katharina Sahm ^{5, 6, 7, 8}

Iris Oezen ^{5, 6}

Frederik Cichon ^{5, 6}

Daniel Baumann ^{3, 4}

Ahmed Sadik ^{9, 10}

Christiane A. Opitz ^{9, 10}

Hilmar Weinmann ^{1, 2}

Ingo V Hartung ^{1, 2}

Bertolt Kreft ^{1, 2}

Rienk Offringa ^{3, 4, 11, 12}

M. Platten ^{5, 6, 7, 8}

Ilona Gutcher ^{1, 2}

Hide authors affiliations Show authors affiliations: 12 affiliations

Bayer AG

Pharmaceutical Division

DKFZ-Bayer Joint Immunotherapy Laboratory (D220) |

⁴

DKFZ-Bayer Joint Immunotherapy Laboratory |

⁵

German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU), Neuroimmunology and Brain Tumor Immunology

⁶

GERMAN CANCER RESEARCH CENTER |

⁷

Department of Neurology, Medical Faculty Mannheim, MCTN |

⁸

Heidelberg university |

⁹

Brain Cancer Metabolism (B350)

¹⁰

German Cancer Research Center (DKFZ) |

¹¹

Department of surgery

¹²

UNIVERSITY HOSPITAL HEIDELBERG |

Publication type: Journal Article

Publication date: 2023-11-14

BMJ

Journal for ImmunoTherapy of Cancer

scimago Q1

wos Q1

SJR: 4.220

CiteScore: 17.8

Impact factor: 10.6

ISSN: 20511426

DOI: 10.1136/jitc-2023-007495

Copy DOI

PubMed ID: 37963637

Cancer Research

Oncology

Pharmacology

Molecular Medicine

Immunology

Immunology and Allergy

Abstract

Background

The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway of constitutive and adaptive tumor immune resistance. The immunosuppressive effects of KYN in the tumor microenvironment are predominantly mediated by the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that broadly suppresses immune cell function. Inhibition of AhR thus offers an antitumor therapy opportunity via restoration of immune system functions.

Methods

The expression of AhR was evaluated in tissue microarrays of head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). A structure class of inhibitors that block AhR activation by exogenous and endogenous ligands was identified, and further optimized, using a cellular screening cascade. The antagonistic properties of the selected AhR inhibitor candidate BAY 2416964 were determined using transactivation assays. Nuclear translocation, target engagement and the effect of BAY 2416964 on agonist-induced AhR activation were assessed in human and mouse cancer cells. The immunostimulatory properties on gene and cytokine expression were examined in human immune cell subsets. The in vivo efficacy of BAY 2416964 was tested in the syngeneic ovalbumin-expressing B16F10 melanoma model in mice. Coculture of human H1299 NSCLC cells, primary peripheral blood mononuclear cells and fibroblasts mimicking the human stromal-tumor microenvironment was used to assess the effects of AhR inhibition on human immune cells. Furthermore, tumor spheroids cocultured with tumor antigen-specific MART-1 T cells were used to study the antigen-specific cytotoxic T cell responses. The data were analyzed statistically using linear models.

Results

AhR expression was observed in tumor cells and tumor-infiltrating immune cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and selectively inhibited AhR activation induced by either exogenous or endogenous AhR ligands. In vitro, BAY 2416964 restored immune cell function in human and mouse cells, and furthermore enhanced antigen-specific cytotoxic T cell responses and killing of tumor spheroids. In vivo, oral application with BAY 2416964 was well tolerated, induced a proinflammatory tumor microenvironment, and demonstrated antitumor efficacy in a syngeneic cancer model in mice.

Conclusions

These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers.

Found

1 citation

Zůvalová Iveta

24 publications, 470 citations

h-index: 14

Palacký University Olomouc

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Kober C. et al. Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy // Journal for ImmunoTherapy of Cancer. 2023. Vol. 11. No. 11. p. e007495.

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RIS |

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RIS Copy

TY - JOUR

DO - 10.1136/jitc-2023-007495

UR - https://doi.org/10.1136/jitc-2023-007495

TI - Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy

T2 - Journal for ImmunoTherapy of Cancer

AU - Kober, Christina

AU - Roewe, Julian

AU - Schmees, Norbert

AU - Roese, Lars

AU - Roehn, Ulrike

AU - Bader, Benjamin

AU - Stoeckigt, Detlef

AU - Prinz, Florian

AU - Gorjánácz, Mátyás

AU - Roider, Helge Gottfried

AU - Olesch, Catherine

AU - Leder, Gabriele

AU - Irlbacher, Horst

AU - Lesche, Ralf

AU - Lefranc, Julien

AU - Oezcan-Wahlbrink, Mine

AU - Batra, Ankita Sati

AU - Elmadany, Nirmeen

AU - Carretero, Rafael

AU - Sahm, Katharina

AU - Oezen, Iris

AU - Cichon, Frederik

AU - Baumann, Daniel

AU - Sadik, Ahmed

AU - Opitz, Christiane A.

AU - Weinmann, Hilmar

AU - Hartung, Ingo V

AU - Kreft, Bertolt

AU - Offringa, Rienk

AU - Platten, M.

AU - Gutcher, Ilona

PY - 2023

DA - 2023/11/14

PB - BMJ

SP - e007495

IS - 11

VL - 11

PMID - 37963637

SN - 2051-1426

ER -

BibTex |

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BibTex (up to 50 authors) Copy

@article{2023_Kober,

author = {Christina Kober and Julian Roewe and Norbert Schmees and Lars Roese and Ulrike Roehn and Benjamin Bader and Detlef Stoeckigt and Florian Prinz and Mátyás Gorjánácz and Helge Gottfried Roider and Catherine Olesch and Gabriele Leder and Horst Irlbacher and Ralf Lesche and Julien Lefranc and Mine Oezcan-Wahlbrink and Ankita Sati Batra and Nirmeen Elmadany and Rafael Carretero and Katharina Sahm and Iris Oezen and Frederik Cichon and Daniel Baumann and Ahmed Sadik and Christiane A. Opitz and Hilmar Weinmann and Ingo V Hartung and Bertolt Kreft and Rienk Offringa and M. Platten and Ilona Gutcher and others},

title = {Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy},

journal = {Journal for ImmunoTherapy of Cancer},

year = {2023},

volume = {11},

publisher = {BMJ},

month = {nov},

url = {https://doi.org/10.1136/jitc-2023-007495},

number = {11},

pages = {e007495},

doi = {10.1136/jitc-2023-007495}

}

MLA

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MLA Copy

Kober, Christina, et al. “Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy.” Journal for ImmunoTherapy of Cancer, vol. 11, no. 11, Nov. 2023, p. e007495. https://doi.org/10.1136/jitc-2023-007495.

Publisher

BMJ

Journal

Journal for ImmunoTherapy of Cancer

scimago Q1

wos Q1

SJR

4.220

CiteScore

17.8

Impact factor

10.6

ISSN

20511426 (Print, Electronic)