title: 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers.
abstract: Resistance to chemotherapy is a major obstacle in the effective treatment of cancer patients. B7-homolog 1, also known as programmed death ligand-1 (PD-L1), is an immunoregulatory protein that is overexpressed in several human cancers. Interaction of B7-H1 with programmed death 1 (PD-1) prevents T-cell activation and proliferation, sequestering the T-cell receptor from the cell membrane, inducing T-cell apoptosis, thereby leading to cancer immunoresistance. B7-H1 upregulation contributes to chemoresistance in several types of cancer, but little is known with respect to changes associated with 5-fluorouracil (5-FU) or gastrointestinal cancers.
  
  
  
  HCT 116 p53+/+, HCT 116 p53-/-colorectal cancer (CRC) and OE33 esophageal adenocarcinoma (EAC) cells were treated with increasing doses of 5-FU (0.5 uM, 5 uM, 50 uM, 500 uM) or interferon gamma (IFN-γ, 10 ng/mL) in culture for 24 h and B7-H1 expression was quantified using flow cytometry and western blot analysis. We also evaluated B7-H1 expression, by immunohistochemistry, in tissue collected prior to and following neoadjuvant therapy in 10 EAC patients.
  
  
  
  B7-H1 expression in human HCT 116 p53+/+and HCT 116 p53-/-CRC cells lines, while low at baseline, can be induced by treatment with 5-FU. OE33 baseline B7-H1 expression exceeded CRC cell maximal expression and could be further increased in a dose dependent manner following 5-FU treatment in the absence of immune cells. We further demonstrate tumor B7-H1 expression in esophageal adenocarcinoma patient-derived pre-treatment biopsies. While B7-H1 expression was not enhanced in post-treatment esophagectomy specimens, this may be due to the limits of immunohistochemical quantification.
  
  
  
  B7-H1/PD-L1 expression can be increased following treatment with 5-FU in gastrointestinal cancer cell lines, suggesting alternative mechanisms to classic immune-mediated upregulation. This suggests that combining 5-FU treatment with PD-1/B7-H1 blockade may improve treatment in patients with gastrointestinal adenocarcinoma.
authors: Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: Lauren
authors: L
authors: Van Der Kraak
authors: Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA USA.|Current address: Division of Medical Oncology, University of Kentucky Markey Cancer Center, Lexington, KY USA.
authors: Gaurav
authors: G
authors: Goel
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: Krishnaveni
authors: K
authors: Ramanan
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: Christof
authors: C
authors: Kaltenmeier
authors: Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
authors: Lin
authors: L
authors: Zhang
authors: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA USA.
authors: Daniel P
authors: DP
authors: Normolle
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA USA.
authors: Gordon J
authors: GJ
authors: Freeman
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: Daolin
authors: D
authors: Tang
authors: Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: Katie S
authors: KS
authors: Nason
authors: Department of Pathology, University of Pittsburgh, Pittsburgh, PA USA.
authors: Jon M
authors: JM
authors: Davison
authors: Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: James D
authors: JD
authors: Luketich
authors: Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA USA.
authors: Rajeev
authors: R
authors: Dhupar
authors: Department of Surgery, University of Pittsburgh, Pittsburgh, PA USA.|Department of Immunology, University of Pittsburgh, Pittsburgh, PA USA.|Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA USA.
authors: Michael T
authors: MT
authors: Lotze
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; D005472:Fluorouracil
keywords: 5-Fluorouracil; B7-H1; Checkpoint blockade; Digestive cancers; Immunotherapy; PD-1; PD-L1