Department of Medical Oncology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Oncol Rep. 2017 Oct;38(4):2189-2196. doi: 10.3892/or.2017.5876. Epub 2017 Aug 3.
Immune checkpoint mechanisms such as the programmed cell death-ligand 1-programmed cell death 1 (PD‑L1-PD‑1) axis are utilized by tumor cells to evade the cytotoxicity of effector immune cells. However, environmental factors responsible for the expression of PD‑L1 on tumor cells remain to be fully elucidated. We hypothesized that an immunological interaction with tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) would contribute to PD‑L1 expression in tumor cells. To verify this hypothesis, we examined the effect of interferon-γ (IFN-γ), a cytokine secreted by CD8+ TILs, on PD‑L1 expression in pulmonary squamous cell carcinomas in vitro. We also evaluated the expression of PD‑L1 and major histocompatibility complex (MHC) class I molecules on tumor cells and CD8+ TILs in squamous cell carcinomas of the lung (n=77) by immunohistochemistry. IFN-γ upregulated PD‑L1 expression on pulmonary squamous carcinoma cells, and the reaction was reversible. In cases where which MHC class I molecule-positive tumor cells were dominant (n=72, 93.5%), cases in which PD‑L1-positive tumor cells were dominant (PD‑L1+ tumor cell‑dominant cases; n=45) were more frequently observed than PD‑L1-negative tumor cell‑dominant cases (n=27) (P=0.006). The number of CD8+ TILs was significantly higher in PD‑L1+ tumor cell‑dominant cases compared with PD‑L1- tumor cell‑dominant cases (P=0.005). These data suggest that the de novo expression of PD‑L1 on tumor cells is upregulated by IFN-γ secreted from CD8+ TILs upon recognition of the tumor cells with an MHC class I molecule.
免疫检查点机制，如程序性细胞死亡配体 1-程序性细胞死亡 1（PD-L1-PD-1）轴，被肿瘤细胞用来逃避效应免疫细胞的细胞毒性。然而，负责肿瘤细胞 PD-L1 表达的环境因素仍有待充分阐明。我们假设与肿瘤浸润的 CD8+淋巴细胞（CD8+TILs）的免疫相互作用将有助于肿瘤细胞中 PD-L1 的表达。为了验证这一假设，我们在体外研究了干扰素-γ（IFN-γ），一种由 CD8+TILs 分泌的细胞因子，对肺鳞状细胞癌中 PD-L1 表达的影响。我们还通过免疫组织化学法评估了 77 例肺鳞状细胞癌中肿瘤细胞和 CD8+TILs 上 PD-L1 和主要组织相容性复合体（MHC）I 类分子的表达。IFN-γ上调肺鳞状癌细胞上的 PD-L1 表达，且该反应是可逆的。在 MHC I 类分子阳性肿瘤细胞占主导地位的情况下（n=72，93.5%），PD-L1 阳性肿瘤细胞占主导地位的病例（PD-L1+肿瘤细胞主导病例；n=45）比 PD-L1 阴性肿瘤细胞主导病例（n=27）更常见（P=0.006）。PD-L1+肿瘤细胞主导病例的 CD8+TILs 数量明显高于 PD-L1-肿瘤细胞主导病例（P=0.005）。这些数据表明，在 MHC I 类分子识别肿瘤细胞后，CD8+TILs 分泌的 IFN-γ上调了肿瘤细胞上 PD-L1 的从头表达。
