title: CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia.
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.
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Semaan
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Bonn, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, University of Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Bergheim
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Bonn, Bonn, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany.
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Kalff
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Branchi
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Matthaei
authors.affiliation: Institute of Pathology, University of Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Pathology, University of Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.affiliation: Institute of Pathology, University of Bonn, Sigmund Freud Str. 25, 53105, Bonn, Germany. diane.goltz@uni-bonn.de.
authors.forename: Diane
authors.initials: D
authors.lastname: Goltz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality* / Q000628:therapy; D054377:Chemokine CXCL12 / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D005260:Female; D006498:Hepatectomy; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D000077157:Sorafenib; D016019:Survival Analysis; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: CXCL12; Hepatocellular carcinoma; Hypoxia; Immune checkpoint inhibitor PD-L1; Tumour-infiltrating lymphocytes