乳头状肾细胞癌 (pRCC) 是最常见的非透明细胞肾细胞癌，与转移情况下的不良预后相关。在本研究中，我们旨在全面评估转移性 pRCC 患者很大程度上未知的免疫肿瘤微环境 (TME)，并确定潜在的治疗靶点。我们使用微环境细胞群计数器 (MCP-counter) 对 TME 进行定量基因表达分析方法，对两个独立的局部 pRCC 队列（n=271 和 n=98）进行研究。然后，我们使用免疫组织化学 (n=38) 和 RNA 测序 (RNA-seq) (n=30) 对来自前瞻性 AXIPAP 试验队列的转移性 pRCC 进行 TME 特征分析。无监督聚类在每个样本中识别出两种“TME 亚型”队列：“免疫增强”和“免疫低”。在 AXIPAP 试验队列中，根据 8 个月（95% CI，6 至 29）与 37 个月（95% CI，20 至 NA，p）的中位总生存期，“免疫丰富”簇与较差的预后显着相关。 =0.001）。 Teff 和 JAVELIN Renal 101 免疫特征这两种免疫特征可预测透明细胞 RCC 中免疫检查点抑制剂 (CPI) 的反应，在“免疫富集”组中显着较高（调整后 p<0.05）。最后，鉴定出五个差异过表达的基因，主要对应于 B 淋巴细胞群体。我们首次使用 RNA-seq 和免疫组织化学，强调了转移性 pRCC 的特定免疫 TME 亚型，其中 T 和 B 免疫群体的浸润明显更多。这个“免疫丰富”组似乎预后较差，并且可能对免疫治疗的反应具有潜在的预测价值，证明了在接受 CPI 并联合靶向治疗治疗的转移性 pRCC 队列中证实这些结果的合理性。NCT02489695.©作者（或其雇主）2023。根据 CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。由英国医学杂志出版。

Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets.We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort.Unsupervised clustering identified two "TME subtypes", in each of the cohorts: the "immune-enriched" and the "immune-low". Within AXIPAP trial cohort, the "immune-enriched" cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the "immune-enriched" group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations.For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This "immune-enriched" group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies.NCT02489695.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.