5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers

Lauren Van Der Kraak, Gaurav Goel, Krishnaveni Ramanan, Christof Kaltenmeier, Lin Zhang, Daniel P. Normolle, Gordon J. Freeman, Daolin Tang, Katie S. Nason, Jon M. Davison, James D. Luketich, Rajeev Dhupar, Michael T. Lotze

Research output: Contribution to journalArticle

25 Citations (Scopus)

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, 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.

Original languageEnglish (US)
Article number65
JournalJournal for ImmunoTherapy of Cancer
Volume4
Issue number1
DOIs
StatePublished - Oct 18 2016
Externally publishedYes

Fingerprint

Gastrointestinal Neoplasms
Fluorouracil
Up-Regulation
Ligands
Adenocarcinoma
Colorectal Neoplasms
Therapeutics
Neoplasms
T-Lymphocytes
Cell Line
Neoadjuvant Therapy
Esophagectomy
T-Cell Antigen Receptor
Interferon-gamma
Flow Cytometry
Western Blotting
Immunohistochemistry
Cell Proliferation
Cell Membrane
Apoptosis

Keywords

  • 5-Fluorouracil
  • B7-H1
  • Checkpoint blockade
  • Digestive cancers
  • Immunotherapy
  • PD-1
  • PD-L1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Van Der Kraak, L., Goel, G., Ramanan, K., Kaltenmeier, C., Zhang, L., Normolle, D. P., ... Lotze, M. T. (2016). 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers. Journal for ImmunoTherapy of Cancer, 4(1), [65]. https://doi.org/10.1186/s40425-016-0163-8

5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers. / 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.

In: Journal for ImmunoTherapy of Cancer, Vol. 4, No. 1, 65, 18.10.2016.

Research output: Contribution to journalArticle

Van Der Kraak, L, Goel, G, Ramanan, K, Kaltenmeier, C, Zhang, L, Normolle, DP, Freeman, GJ, Tang, D, Nason, KS, Davison, JM, Luketich, JD, Dhupar, R & Lotze, MT 2016, '5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers', Journal for ImmunoTherapy of Cancer, vol. 4, no. 1, 65. https://doi.org/10.1186/s40425-016-0163-8
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. / 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers. In: Journal for ImmunoTherapy of Cancer. 2016 ; Vol. 4, No. 1.
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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, 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.",
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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.

PY - 2016/10/18

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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.

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KW - 5-Fluorouracil

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KW - Digestive cancers

KW - Immunotherapy

KW - PD-1

KW - PD-L1

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