Machine-learning based integrating bulk and single-cell RNA sequencing reveals the SLC38A5-CCL5 signaling as a promising target for clear cell renal cell carcinoma treatment

Hualin Chen; Wenjie Yang; Lin Ma; Yingjie Li; Zhigang Ji

doi:10.1016/j.tranon.2023.101790

Machine-learning based integrating bulk and single-cell RNA sequencing reveals the SLC38A5-CCL5 signaling as a promising target for clear cell renal cell carcinoma treatment

Transl Oncol. 2023 Dec:38:101790. doi: 10.1016/j.tranon.2023.101790. Epub 2023 Sep 17.

Authors

Hualin Chen¹, Wenjie Yang¹, Lin Ma¹, Yingjie Li¹, Zhigang Ji²

Affiliations

¹ Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
² Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China. Electronic address: jizhigang@pumch.cn.

Abstract

Cancer-associated fibroblasts paly critical roles in regulating cancer cell biological properties by intricate and dynamic communication networks. But the mechanism of CAFs in clear cell renal cell carcinoma (ccRCC) is not clear. In our study, we identified CAFs and malignant cells from the integrated scRNA-seq datasets and establish a CAF-derived communication signature based on the highly activated regulons ETS1 and MEF2C. We stratified the ccRCC TME into two molecular subtypes with distinct prognoses, immune cell infiltration landscapes, and immune-related characteristics. The model derived from signature demonstrated high accuracy and robustness in predicting prognosis and ICIs therapy responses. Subsequently, the SLC38A5 of the model was found upregulated in CAFs and was related to decreased survival probabilities, inflamed TME, and upregulated inhibitory checkpoints. SLC38A5 inhibition could attenuate the pro-tumoral abilities of CAFs in terms of proliferation, migration, and invasion. Mechanically, CCL5 could restore these properties induced by SLC38A5 inhibition. In conclusion, our communication signature and its derived model enabled a more precise selection of ccRCC patients who were potential beneficiaries of ICIs. Besides, the SLC38A5-CCL5 axis may serve as a promising target for ccRCC treatment.

Keywords: Cancer-associated fibroblast; Clear cell renal cell carcinoma; Immunotherapy; SlC38A5; Tumor microenvironment.