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CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia

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Abstract

Anti-PD-1 treatment increases anti-tumour immune responses in animal models of hepatocellular carcinoma (HCC). Sorafenib, the mainstay of treatment of HCC patients, however, leads to tumour hypoxia and thereby abrogates the efficacy of anti-PD-1 treatment. This served as a rationale to implement CXCR4 inhibition as adjunct to sorafenib and anti-PD-1 treatment in murine HCC models. We studied the relationship between tumour hypoxia, PD-L1 and CXCL12 expression in human HCC, aiming to test the rationale for triple therapy combining sorafenib, PD-1 immune checkpoint inhibitors and CXCR4 inhibitors. Expression of CXCL12, PD-L1 and of surrogate markers for tumour hypoxia was evaluated at messenger RNA (mRNA) level in a cohort of HCC patients from The Cancer Genome Atlas and immunohistochemically in an independent cohort from the University Hospital of Bonn. Retrospective survival analyses were conducted. CXCL12 mRNA level significantly correlated with markers indicating tumour hypoxia in HCC (HIF1-α ρ = 0.104, p = 0.047). PD-L1 expression was significantly increased in tumours with a high number of tumour-infiltrating lymphocytes (ρ = 0.533, p < 0.001). In Cox proportional hazard analyses, high PD-L1 expression and loss of nuclear CXCL12 expression showed significant prognostic value in terms of overall survival (hazard ratio (HR) = 3.35 [95%CI 1.33–8.46], p = 0.011 for PD-L1; HR = 2.64 [95%CI 1.18–5.88], p = 0.018 for CXCL12, respectively). This study supports the rationale to combine CXCR4 inhibitors and PD-1 immune checkpoint inhibitors in patients with HCC, as sorafenib-induced tumour hypoxia leads to upregulation of PD-L1 and CXCL12.

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Authors and Affiliations

  1. Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany

    Alexander Semaan, Jörg C. Kalff, Vittorio Branchi & Hanno Matthaei

  2. Department of Otolaryngology, Head and Neck Surgery, University of Bonn, Bonn, Germany

    Dimo Dietrich & Jörn Dietrich

  3. Institute of Pathology, University of Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany

    Dominik Bergheim, Glen Kristiansen, Hans-Peter Fischer & Diane Goltz

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  1. Alexander Semaan
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  2. Dimo Dietrich
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Correspondence to Diane Goltz.

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This study has been approved by the Institutional Review Board (IRB) of the University Hospital of Bonn (No. 167/16). Informed consent has been obtained from all patients that were included in the TCGA cohort in accordance with the Helsinki Declaration of 1975.

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The authors declare that they have no conflict of interest.

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Alexander Semaan, Dimo Dietrich, Hans-Peter Fischer and Diane Goltz have equal contribution.

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Semaan, A., Dietrich, D., Bergheim, D. et al. CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia. Virchows Arch 470, 185–196 (2017). https://doi.org/10.1007/s00428-016-2051-5

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