Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA USA.
Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA USA.
J Immunother Cancer. 2016 Oct 18;4:65. doi: 10.1186/s40425-016-0163-8. eCollection 2016.
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.
背景：化疗耐药是癌症患者有效治疗的主要障碍。B7 同源物 1 也称为程序性死亡配体 1（PD-L1），是一种免疫调节蛋白，在几种人类癌症中过度表达。B7-H1 与程序性死亡 1（PD-1）的相互作用可阻止 T 细胞激活和增殖，将 T 细胞受体从细胞膜上隔离出来，诱导 T 细胞凋亡，从而导致癌症免疫抵抗。B7-H1 的上调有助于几种类型的癌症的化疗耐药，但对于与 5-氟尿嘧啶（5-FU）或胃肠道癌症相关的变化知之甚少。
方法：将 HCT 116 p53、HCT 116 p53 结直肠癌（CRC）和 OE33 食管腺癌（EAC）细胞分别用不同剂量的 5-FU（0.5 μM、5 μM、50 μM、500 μM）或干扰素 γ（IFN-γ，10 ng/mL）在培养物中处理 24 小时，并用流式细胞术和 Western blot 分析定量 B7-H1 表达。我们还通过免疫组织化学法评估了 10 例 EAC 患者新辅助治疗前后组织中的 B7-H1 表达。
结果：人类 HCT 116 p53 和 HCT 116 p53 CRC 细胞系中 B7-H1 的表达水平较低，但在基线时可以通过 5-FU 处理诱导。OE33 细胞系的 B7-H1 表达基线超过 CRC 细胞系的最大表达水平，并且在没有免疫细胞的情况下，5-FU 处理后可以呈剂量依赖性进一步增加。我们进一步证明了食管腺癌患者来源的预处理活检中的肿瘤 B7-H1 表达。虽然治疗后食管癌标本中的 B7-H1 表达没有增强，但这可能是由于免疫组织化学定量的局限性。
结论：在胃肠道癌细胞系中用 5-FU 治疗后，B7-H1/PD-L1 的表达可以增加，这表明存在与经典免疫介导的上调不同的机制。这表明在胃肠道腺癌患者中联合 5-FU 治疗和 PD-1/B7-H1 阻断可能会改善治疗效果。
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