Department of Ocular Pathology, Dr. R P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, USA.
Cancer Immunol Immunother. 2021 May;70(5):1291-1303. doi: 10.1007/s00262-020-02773-8. Epub 2020 Nov 2.
To understand how to improve the effect of immune checkpoint inhibitors in uveal melanoma (UM), we need a better understanding of the expression of PD-1 and PD-L1, their relation with the presence of tumor-infiltrating lymphocytes (TILs), and their prognostic relevance in UM patients.
Expression of PD-1 and PD-L1 was assessed in 71 UM tissue samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and further validated by western blotting. The effect of interferon gamma (IFN-γ) on PD-1/PD-L1 expression was determined on four UM cell lines.
Immunoreactivity of PD-1 was found in 30/71 cases and of PD-L1 in 44/71 UM samples. Tumor-infiltrating lymphocytes were found in 46% of UM tissues. PD-1 was expressed on TILs while tumor cells expressed PD-L1. UM with and without TILs showed expression of PD-1 in 69% and 18% cases, respectively (p = 0.001). Similarly, PD-L1 was found in 75% of UM with TILs and in 50% of cases without TILs, respectively (p = 0.03). DFS rate were lower in patients with TILs with expression of PD-1 and PD-L1, but the rate of DFS was higher with expression of PD-L1 in patients without TILs. After treatment of UM cell lines with IFN-γ, PD-1 expression was induced in all UM cell lines whereas PD-L1 expression was found at a lower level in untreated cells, while expression also increased following treatment with IFN-γ.
Our study suggests that increased infiltration with TILs promotes the aggressive behavior and suppresses the immune response of UM cells, thereby inhibiting immunotherapy.
为了了解如何提高免疫检查点抑制剂在葡萄膜黑色素瘤（UM）中的疗效，我们需要更好地了解 PD-1 和 PD-L1 的表达、它们与肿瘤浸润淋巴细胞（TILs）的存在的关系，以及它们在 UM 患者中的预后相关性。
通过免疫组织化学和实时定量 PCR（qRT-PCR）评估了 71 例 UM 组织样本中 PD-1 和 PD-L1 的表达，并通过 Western blot 进一步验证。测定干扰素γ（IFN-γ）对四种 UM 细胞系中 PD-1/PD-L1 表达的影响。
在 71 例 UM 样本中，有 30 例检测到 PD-1 免疫反应性，44 例检测到 PD-L1 免疫反应性。在 46%的 UM 组织中发现了肿瘤浸润淋巴细胞。TILs 表达 PD-1，而肿瘤细胞表达 PD-L1。有和没有 TILs 的 UM 分别有 69%和 18%的病例表达 PD-1（p=0.001）。同样，有 TILs 的 UM 中有 75%和没有 TILs 的 UM 中有 50%分别发现 PD-L1 的表达（p=0.03）。在有 TILs 表达 PD-1 和 PD-L1 的患者中，DFS 率较低，但在没有 TILs 表达 PD-L1 的患者中，DFS 率较高。用 IFN-γ处理 UM 细胞系后，所有 UM 细胞系中均诱导表达 PD-1，而未经处理的细胞中 PD-L1 表达水平较低，用 IFN-γ处理后表达也增加。
我们的研究表明，TILs 的浸润增加促进了 UM 细胞的侵袭行为并抑制了免疫反应，从而抑制了免疫治疗。
