Virchows Archiv

, Volume 470, Issue 2, pp 185–196 | Cite as

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

  • Alexander Semaan
  • Dimo Dietrich
  • Dominik Bergheim
  • Jörn Dietrich
  • Jörg C. Kalff
  • Vittorio Branchi
  • Hanno Matthaei
  • Glen Kristiansen
  • Hans-Peter Fischer
  • Diane Goltz
Original Article


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.


Immune checkpoint inhibitor PD-L1 Hepatocellular carcinoma CXCL12 Hypoxia Tumour-infiltrating lymphocytes 


Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Alexander Semaan
    • 1
  • Dimo Dietrich
    • 2
  • Dominik Bergheim
    • 3
  • Jörn Dietrich
    • 2
  • Jörg C. Kalff
    • 1
  • Vittorio Branchi
    • 1
  • Hanno Matthaei
    • 1
  • Glen Kristiansen
    • 3
  • Hans-Peter Fischer
    • 3
  • Diane Goltz
    • 3
  1. 1.Department of General, Visceral, Thoracic and Vascular SurgeryUniversity of BonnBonnGermany
  2. 2.Department of Otolaryngology, Head and Neck SurgeryUniversity of BonnBonnGermany
  3. 3.Institute of PathologyUniversity of BonnBonnGermany

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