TY - JOUR
T1 - 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers
AU - Van Der Kraak, Lauren
AU - Goel, Gaurav
AU - Ramanan, Krishnaveni
AU - Kaltenmeier, Christof
AU - Zhang, Lin
AU - Normolle, Daniel P.
AU - Freeman, Gordon J.
AU - Tang, Daolin
AU - Nason, Katie S.
AU - Davison, Jon M.
AU - Luketich, James D.
AU - Dhupar, Rajeev
AU - Lotze, Michael T.
N1 - Funding Information:
This project is supported by charitable contributions to the Center for DAMP Biology at the University of Pittsburgh. Analysis of flow results utilized the UPCI Cytometry Shared Resource Facility, and data analysis was supported by the UPCI Biostatistics Shared Resource Facility, both of which are supported in part by an award to the UPCI Core Support (P30CA047904). KSN is supported by Award Number K07CA151613 from the National Cancer Institute at the National Institutes of Health. The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute or the National Institutes of Health.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/10/18
Y1 - 2016/10/18
N2 - 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, 10ng/mL) in culture for 24h 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.
AB - 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, 10ng/mL) in culture for 24h 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.
KW - 5-Fluorouracil
KW - B7-H1
KW - Checkpoint blockade
KW - Digestive cancers
KW - Immunotherapy
KW - PD-1
KW - PD-L1
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UR - http://www.scopus.com/inward/citedby.url?scp=84997795544&partnerID=8YFLogxK
U2 - 10.1186/s40425-016-0163-8
DO - 10.1186/s40425-016-0163-8
M3 - Article
C2 - 27777774
AN - SCOPUS:84997795544
SN - 2051-1426
VL - 4
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 1
M1 - 65
ER -