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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1305-1315
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume67
Issue number8
DOIs
StatePublished - 1 Aug 2018

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Hepatocellular Carcinoma
Neoplasms
Therapeutics
Antibodies
Standard of Care
Up-Regulation
Liver

Keywords

  • Adaptive resistance
  • CTLA-4
  • Hepatocellular carcinoma
  • IDO
  • PD-1

Cite this

Brown, Zachary J. ; Yu, Su Jong ; Heinrich, Bernd ; Ma, Chi ; Fu, Qiong ; Sandhu, Milan ; Agdashian, David ; Zhang, Qianfei ; Korangy, Firouzeh ; Greten, Tim F. / Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. In: Cancer Immunology, Immunotherapy. 2018 ; Vol. 67, No. 8. pp. 1305-1315.
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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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Brown, ZJ, Yu, SJ, Heinrich, B, Ma, C, Fu, Q, Sandhu, M, Agdashian, D, Zhang, Q, Korangy, F & Greten, TF 2018, 'Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma', Cancer Immunology, Immunotherapy, vol. 67, no. 8, pp. 1305-1315. https://doi.org/10.1007/s00262-018-2190-4

Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. / Brown, Zachary J.; Yu, Su Jong; Heinrich, Bernd; Ma, Chi; Fu, Qiong; Sandhu, Milan; Agdashian, David; Zhang, Qianfei; Korangy, Firouzeh; Greten, Tim F.

In: Cancer Immunology, Immunotherapy, Vol. 67, No. 8, 01.08.2018, p. 1305-1315.

Research output: Contribution to journalArticle

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AU - Brown, Zachary J.

AU - Yu, Su Jong

AU - Heinrich, Bernd

AU - Ma, Chi

AU - Fu, Qiong

AU - Sandhu, Milan

AU - Agdashian, David

AU - Zhang, Qianfei

AU - Korangy, Firouzeh

AU - Greten, Tim F.

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