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

Abstract

BackgroundResistance 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.MethodsHCT 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.ResultsB7-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.ConclusionsB7-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.

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

“…The differences observed in the positivity rate of PD-L1 in ESCC may be attributed to the antibodies used in the IHC staining and the scoring criteria for the staining. The positivity rate of PD-L1 is also dependent on whether the patients received any treatment before sample collection since chemotherapy and radiotherapy induce PD-L1 expression, as demonstrated by our current study and other reports [8], [26], [27]. Previous studies demonstrate that high PD-L1 expression is associated with advanced disease and lymph node metastasis in various cancers [28], [29], [30].…”

Immunoregulatory influence of abundant MFG‐E8 expression by esophageal cancer treated with chemotherapy

“…In the current study, there was a significantly higher rate of high MFG‐E8 expression in the tumors of patients treated with NAC compared with those not treated with NAC. Immune checkpoint molecules, such as PD‐1, cytotoxic T‐lymphocyte associated protein‐4 and PD‐1 ligand (PD‐L1), have been suggested to increase after chemotherapy . We hypothesized that MFG‐E8 also might be induced by preoperative chemotherapy in esophageal cancer cells.…”

“…Immune checkpoint molecules, such as PD-1, cytotoxic T-lymphocyte associated protein-4 and PD-1 ligand (PD-L1), have been suggested to increase after chemotherapy. 27,38,39 We hypothesized that MFG-E8 also might be induced by preoperative chemotherapy in esophageal cancer cells. year survival rate remains as low as 59.2% among those who showed a good response to therapy.…”

Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma

“…However, cisplatin is known to reduce numbers of circulating immune cells, suggesting it can be directly toxic to immune cells. Tumor cells treated with cytotoxic drugs may upregulate immune checkpoint ligands as a form of immune escape (11, 12). In the current study, we employed preclinical models of head and neck cancer to show that cisplatin may enhance antitumor adaptive immunity by upregulating antigen processing machinery and enhancing tumor cell killing by CD8 + T cells without decreasing T-cell numbers.…”

“…Prior preclinical and clinical studies in other cancer types suggest that cisplatin and other cytotoxic chemotherapy drugs may enhance antitumor immunity by enhancing immunogenic cell death, increasing expression of MHC class I and other components of the antigen processing machinery, enhancing numbers and function of immune effector cells, and decreasing numbers of immunosuppressive cells (7–10). However, other preclinical studies suggest that cytotoxic chemotherapy can upregulate tumor cell expression of PD-L1 (11, 12), potentially impairing antitumor immunity by inducing T-cell anergy.…”