5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers. Issue 1 (18th October 2016)

• Record Type: Journal Article
• Authors: Van Der Kraak, Lauren; Goel, Gaurav; Ramanan, Krishnaveni; Kaltenmeier, Christof; Zhang, Lin; Normolle, Daniel P.; Freeman, Gordon J.; Tang, Daolin; Nason, Katie S.; Davison, Jon M.; Luketich, James D.; Dhupar, Rajeev; Lotze, Michael T.
• Is Part Of: Journal for immunotherapy of cancer. Volume 4:Issue 1(2016)
• Publication Date: 2016-10-18
• Subjects: 5-Fluorouracil -- B7-H1 -- PD-L1 -- PD-1 -- Digestive cancers -- Checkpoint blockade -- Immunotherapy; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-016-0163-8
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: 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. Methods: 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. Results: 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. Conclusions: 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.