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Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies has shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here, we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-γ. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.

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Abbreviations

1-d-MT:

1-methyl-d-tryptophan

BLI:

Bioluminescent imaging

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Acknowledgements

We would like to thank J. Berzofsky and his lab for their helpful discussion. We would also like to thank J.M. Hernandez for advising on performing intra-hepatic injections.

Funding

Tim F. Greten is supported by the NIH intra-mural program (ZIA BC 01134).

Author information

Authors and Affiliations

  1. Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD, 20892, USA

    Zachary J. Brown, Su Jong Yu, Bernd Heinrich, Chi Ma, Qiong Fu, Milan Sandhu, David Agdashian, Qianfei Zhang, Firouzeh Korangy & Tim F. Greten

  2. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Su Jong Yu

  3. National Cancer Institute, Center for Cancer Research, Liver Cancer Program, Bethesda, USA

    Tim F. Greten

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  1. Zachary J. Brown
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Contributions

ZJB, SJY, and BH performed experiments. ZJB, CM, QF, FK, and TFG analyzed data. QF, MS, DA, and QZ assisted with experiments. ZJB and TFG conceived and designed the project. ZJB and TFG wrote the manuscript and all authors contributed to writing and providing feedback.

Corresponding author

Correspondence to Tim F. Greten.

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Conflict of interest

The authors declare they have no conflicts of interest.

Animal experiments

All experiments were performed according to the institutional guidelines and approved by a NCI-Bethesda (Bethesda, MD, USA) Institutional Animal Care and Use protocol. Mice were purchased from Charles River Laboratories (VA, USA) or The Jackson Laboratory (Bar Harbor, USA). Human blood samples (buffy coat) were obtained from the National Institutes of Health Blood Research Services.

Cell lines

RIL-175 cell line was obtained from Dr Lars Zander (University Hospital of Tübingen, Germany), BNL cell line was provided by Dr. Jesus Prieto (University of Navarra, Spain), HepG2 (Cat no: HB-8065) and Hep3B (Cat no: HB-8064) was purchased from ATCC.

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Brown, Z.J., Yu, S.J., Heinrich, B. et al. Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol Immunother 67, 1305–1315 (2018). https://doi.org/10.1007/s00262-018-2190-4

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