Song Xiyu, Zhu Yumeng, Geng Wenwen, Jiao Jianhua, Liu Hongjiao, Chen Ruo, He Qian, Wang Lijuan, Sun Xiuxuan, Qin Weijun, Geng Jiejie, Chen Zhinan
National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
Xijing Innovation Research Institute, Fourth Military Medical University, Xi'an, Shaanxi, China.
J Immunother Cancer. 2025 Jan 4;13(1):e010183. doi: 10.1136/jitc-2024-010183.
Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated.
To further investigate the cellular and regional heterogeneity of ccRCC, we analyzed single-cell and spatial transcriptome RNA sequencing data from four patients, which were obtained from samples from multiple regions, including the tumor core, tumor-normal interface, and distal normal tissue. On the basis, the findings were investigated in vitro using tissue and blood samples from 15 patients with ccRCC and validated in the broader samples on tissue microarrays.
In this study, we revealed previously unreported subsets of both stromal and immune cells, as well as mapped their spatial location at finer resolution. In addition, we validated the clusters of tumor cells after removing batch effects according to six characterized gene sets, including epithelial-mesenchymal transition clusters, metastatic clusters and proximal tubule clusters. Importantly, we identified a special regulatory T (Treg) cell subpopulation that has the molecular characteristics of terminal effector Treg cells but expresses multiple cytokines, such as interleukin (IL)-1β and IL-18. This group of Treg cells has stronger immunosuppressive function and was associated with a worse prognosis in ccRCC cohorts. They were colocalized with tumor-associated macrophages (TAMs) at the tumor-normal interface to form a positive feedback loop, maintaining a synergistic procarcinogenic effect. In addition, we traced the origin of IL-1β Treg cells and revealed that IL-18 can induce the expression of IL-1β in Treg cells via the ERK/NF-κB pathway.
We demonstrated a novel cancer-promoting Treg cell subset and its interactions with TAMs, which provides new insight into Treg cell heterogeneity and potential therapeutic targets for ccRCC.
透明细胞肾细胞癌（ccRCC）是肾细胞癌最常见的组织学类型。然而，免疫抑制细胞的空间和功能异质性及其相互作用促进ccRCC免疫抑制的机制尚未得到充分研究。
为了进一步研究ccRCC的细胞和区域异质性，我们分析了来自4例患者的单细胞和空间转录组RNA测序数据，这些数据取自多个区域的样本，包括肿瘤核心、肿瘤-正常组织界面和远端正常组织。在此基础上，使用15例ccRCC患者的组织和血液样本进行体外研究，并在组织微阵列的更广泛样本中进行验证。
在本研究中，我们揭示了以前未报道的基质细胞和免疫细胞亚群，并以更高分辨率绘制了它们的空间位置。此外，我们根据六个特征基因集（包括上皮-间质转化簇、转移簇和近端小管簇）去除批次效应后，验证了肿瘤细胞簇。重要的是，我们鉴定出一种特殊的调节性T（Treg）细胞亚群，其具有终末效应Treg细胞的分子特征，但表达多种细胞因子，如白细胞介素（IL）-1β和IL-18。这组Treg细胞具有更强的免疫抑制功能，并且与ccRCC队列中更差的预后相关。它们在肿瘤-正常组织界面与肿瘤相关巨噬细胞（TAM）共定位，形成正反馈回路，维持协同促癌作用。此外，我们追踪了IL-1β Treg细胞的起源，并揭示IL-18可通过ERK/NF-κB途径诱导Treg细胞中IL-1β的表达。
我们证明了一种新的促癌Treg细胞亚群及其与TAM的相互作用，这为Treg细胞异质性和ccRCC的潜在治疗靶点提供了新的见解。
