Comprehensive Analysis of Ferroptosis Regulators With Regard to PD-L1 and Immune Infiltration in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is one of the tumor types with sensitivity to ferroptosis, and immunotherapy has emerged as a standard pillar for metastatic ccRCC treatment, while it remains largely obscure whether ferroptosis influences the tumor immune microenvironment in ccRCC. Based on available data in The Cancer Genome Atlas, divergent expression profiles of ferroptosis regulators were noted in ccRCC and normal tissues, and we also found that the ferroptosis regulators correlated with the PD-L1 expression. Two independent subtypes were determined by consensus clustering analysis according to the expression level of ferroptosis regulators in ccRCC. Cluster 1 showed lower histological tumor stage and grade, more favorable prognosis, and higher PD-L1 expression compared to cluster 2. CIBERSORT analysis revealed that cluster 2 harbored higher infiltrated levels of CD8+ T cell, Tregs, and T follicular helper cell, while cluster 1 more correlated with the monocyte, M1 macrophage, and M2 macrophage. Gene set enrichment analysis indicated that the ERBB signaling and JAK_STAT signaling pathways were significantly enriched in cluster 1. We subsequently identified CARS as the potentially key immune infiltration-related ferroptosis regulator, whose high expression showed dismal prognosis and was positively correlated with PD-L1 expression in ccRCC. We also verified the upregulation of CARS in ccRCC tissues and cell lines via qRT-PCR method. Additionally, a pan-cancer analysis demonstrated that CARS closely related to the expression of immune checkpoint-related genes (especially PD-L1) and an unfavorable prognosis in diverse cancer types. In summary, our study suggested the crucial role of ferroptosis in immune infiltration of ccRCC, and CARS is a potentially novel prognostic biomarker and potential target for cancer immunotherapy.

Ferroptosis and Its Potential Role in Lung Cancer: Updated Evidence from Pathogenesis to Therapy

“…Exhaustion of intracellular cystine or blocking of anti-programmed cell death protein 1/programmed death ligand 1 (anti-PD-1/PD-L1) immune checkpoint significantly enhanced T cell-mediated anti-tumor immunity and induced the ferroptosis of tumor cell. 85 At the same time, clinical data showed that among patients with melanin, the expression of cystine associated transporters SLC7A11 and SLC3A2 was negatively correlated with the number of CD8+T cells, IFN-γ expression level and patient prognosis. 86 Despite recently targeting lung cancer, the relationship between T cell and ferroptosis is uncertain.…”

No Time to Die: How Kidney Cancer Evades Cell Death

“…RCC is a tumor with high sensitivity to ferroptosis, and a consensus clustering analysis on data from the TCGA, with regards to ferroptosis regulators, shows two independent clusters with different expressions of PD-L1 and immune infiltrate. The expression of PD-L1 was, therefore, used to understand a possible co-upregulation with a ferroptosis regulator and cysteinyl-tRNA synthetase (CARS), a described inhibitor of ferroptotic cell death shown to be highly expressed by RCC, correlating with the expression of PD-L1 and a worse prognosis and decreased overall survival, showing a possible connection between ferroptosis and the immune network orchestrated by the immune checkpoint molecules in RCC [ 74 ].…”

MicroRNA-4735-3p Facilitates Ferroptosis in Clear Cell Renal Cell Carcinoma by Targeting SLC40A1

“…In addition, the expressions of various ferroptosis-related genes can accurately predict the prognosis and survival outcome in ccRCC patients and are identified as potential prognostic biomarkers and therapeutic targets [ 11 , 13 ]. Moreover, triggering ferroptosis also enhances the efficiency of chemotherapy and immunotherapy for some refractory cases [ 14 , 15 ]. Based on these findings, it is promising and highly desirable to treat human ccRCC through inducing ferroptosis.…”