Single-cell transcriptomics reveals a low CD8 + T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma

作者：Yulu Peng, Longbin Xiong, Zhaohui Zhou, Ning Kang, Zhen Li, Zeshen Wu, Min-Hua Deng, Wen-Su Wei, Ning Wang, Xiang-Peng Zou, Zhisong He, Jiwei Huang, Junhang Luo, Jianye Liu, Nan Jia, Yun Cao, Hui Han, Shengjie Guo, Pei Dong, Chunping Yu, Fangjian Zhou, Zhiling Zhang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2021-004206 · 被引用次数：76 · 研究领域：Single-cell and spatial transcriptomics、Renal cell carcinoma treatment、Cancer Immunotherapy and Biomarkers

Purpose Recurrent renal cell carcinoma(reRCC) is associated with poor prognosis and the underlying mechanism is not yet clear. A comprehensive understanding of tumor microenvironment (TME) of reRCC may aid in designing effective anticancer therapies, including immunotherapies. Single-cell transcriptomics holds great promise for investigating the TME, however, this technique has not been used in reRCC. Here, we aimed to explore the difference in the TME and gene expression pattern between primary RCC (pRCC) and reRCC at single-cell level. Experimental design We performed single-cell RNA sequencing analyses of 32,073 cells from 2 pRCC, 2 reRCC, and 3 adjacent normal kidney samples. 41 pairs of pRCC and reRCC samples were collected as a validation cohort to assess differences observed in single-cell sequencing. The prognostic significance of related cells and markers were studied in 47 RCC patients underwent immunotherapy. The function of related cells and markers were validated via in vitro and in vivo experiments. Results reRCC had reduced CD8 + T cells but increased cancer-associated fibroblasts (CAFs) infiltration compared with pRCC. Reduced CD8 + T cells and increased CAFs infiltration were significantly associated with a worse response from immunotherapy. Remarkably, CAFs showed substantial expression of LGALS1 (Gal1). In vitro, CAFs could induce CD8 + T cells apoptosis via Gal1. In vivo, knockdown of Gal1 in CAFs suppressed tumor growth, increased CD8 + T cells infiltrati...