Cell Differentiation Trajectory Predicts Prognosis and Immunotherapeutic Response in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the main type of malignancy in kidney related to glucose metabolism. Primary single cell culture and single cell sequencing are novel research technologies. In this study, we explored the differentiation status of ccRCC cells and its significance in prognosis and immunotherapeutic response through bioinformatics. We characterized distinct differentiation states and differentiation-related genes (DRGs) in ccRCC cells through single cell RNA sequencing (scRNA-seq) analysis. Combined with bulk RNA-seq data, we classified patients into two clusters and found that this classification was closely correlated with patient prognosis and immunotherapeutic responses. Based on machine learning, we identified a prognostic risk model composed of 14 DRGs, including BTG2, CDKN1A, COL6A1, CPM, CYB5D2, FOSB, ID2, ISG15, PLCG2, SECISBP2, SOCS3, TES, ZBTB16, and ZNF704, to predict the survival rate of patients and then constructed a nomogram model integrating clinicopathological characteristics and risk score for clinical practice. In the study of immune checkpoints, we found that patients in the high-risk group had a disposition to get worse prognosis and better effects of immune checkpoint blocking therapies. Finally, we found the expression level of model DRGs was associated with a tumor-immune microenvironment (TIME) pattern and the response of 83 compounds or inhibitors was significantly different in the two risk groups. In a word, our study highlights the potential contribution of cell differentiation in prognosis judgment and immunotherapy response and offers promising therapeutic options for ccRCC patients.

Deciphering the tumour microenvironment of clear cell renal cell carcinoma: Prognostic insights from programmed death genes using machine learning

“…In the theatre of apoptosis, bid takes center stage, with its malfunction forming the underpinning for oncogenic development and emerging as a credible risk factor in the annals of ccRCC 37 . A previous study found that the emergence of cdkn1a 's antisense DNA damage‐activated RNA promoter as a conspicuous presence in tumour tissues renders it a key protagonist, additionally serving as an independent harbinger of OS in ccRCC 38 . The immunoregulatory gene cx3cl1 emerges as a prominent constituent in the inflammatory milieu of ccRCC, bestowing a pathway to personalized treatment strategies 39 .…”

“… 37 A previous study found that the emergence of cdkn1a 's antisense DNA damage‐activated RNA promoter as a conspicuous presence in tumour tissues renders it a key protagonist, additionally serving as an independent harbinger of OS in ccRCC. 38 The immunoregulatory gene cx3cl1 emerges as a prominent constituent in the inflammatory milieu of ccRCC, bestowing a pathway to personalized treatment strategies. 39 ddias , when overexpressed in NCI‐H1299 or NCI‐H1703 cells, assumes an inhibitory role, counteracting the proliferation induced by CHIP overexpression.…”