INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for patients with clear cell renal cell carcinoma (ccRCC), but not all patients benefit from ICI. One reason is the tumor microenvironment (TME) that has substantial influence on patient's prognosis and therapy response. Thus, we comprehensively analyzed the TME of ccRCC regarding prognostic and predictive properties. METHODS: Tumor-infiltrating CD3-positive T-cells, CD8-positive cytotoxic T-lymphocytes (CTLs), regulatory T-cells, B-cells, plasma cells, macrophages, granulocytes, programmed cell death receptor 1 (PD-1), and its ligand PD-L1 were examined in a large hospital-based series of ccRCC with long-term follow-up information (n = 756) and in another patient collective with information on response to nivolumab therapy (n = 8). Tissue microarray technique and digital image analysis were used. Relationship between immune cell infiltration and tumor characteristics, cancer-specific survival (CSS), or response to ICI was examined. RESULTS: Univariate survival analysis revealed that increased tumor-infiltrating B-cells, T-cells, and PD-1-positive cells were significantly associated with favorable CSS and high levels of intratumoral granulocytes, macrophages, cytotoxic T-cells, and PD-L1 significantly with poor CSS. High CTL or B-cell infiltration and high PD-L1 expression of ccRCC tumor cells qualified as independent prognostic biomarkers for patients' CSS. Significantly higher densities of intratumoral T-cells, CTLs, and PD-1-positive immune cells were observed in ccRCC with response to ICI compared with patients with mixed or no response (CD3: p = 0.003; CD8: p = 0.006; PD-1: p = 0.01). DISCUSSION: This study shows that subsets of tumor-infiltrating leukocytes in the TME and also PD-1/PD-L1 provide prognostic and predictive information for patients with ccRCC.

简介：免疫检查点抑制剂（ICI）已被批准用于患有透明细胞肾细胞癌（ccRCC）的患者，但并非所有患者都能从ICI中受益。原因之一是肿瘤微环境（TME）对患者的预后和治疗反应具有重大影响。因此，我们对ccRCC的TME进行了预后和预测方面的综合分析。方法：肿瘤浸润性CD3阳性T细胞，CD8阳性细胞毒性T淋巴细胞（CTL），调节性T细胞，B细胞，浆细胞，巨噬细胞，粒细胞，程序性细胞死亡受体1（PD-1）及其在大型的ccRCC医院系列中对配体PD-L1进行了检查，并获得了长期随访信息（n = 756），在另一名患者身上收集了有关对nivolumab治疗反应的信息（n = 8）。使用组织微阵列技术和数字图像分析。检查了免疫细胞浸润与肿瘤特征，癌症特异性生存率（CSS）或对ICI反应之间的关系。结果：单因素生存分析显示，增加的肿瘤浸润B细胞，T细胞和PD-1阳性细胞与良好的CSS显着相关，并且高水平的肿瘤内粒细胞，巨噬细胞，细胞毒性T细胞和PD-L1与可怜的CSS。ccRCC肿瘤细胞的高CTL或B细胞浸润​​和高PD-L1表达可作为患者CSS的独立预后生物标志物。在ccRCC中，对ICI有反应的患者中，肿瘤内T细胞，CTL和PD-1阳性免疫细胞的密度明显高于无反应或无反应的患者（CD3：p = 0.003； CD8：p = 0.006； PD- 1：p = 0.01）。讨论： 这项研究表明，TME中的肿瘤浸润白细胞子集以及PD-1 / PD-L1为ccRCC患者提供了预后和预测信息。