Identification of Ligand-Receptor Pairs Associated With Tumour Characteristics in Clear Cell Renal Cell Carcinoma

Abstract

The tumour microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) comprises multiple cell types, which promote tumour progression and modulate drug resistance and immune cell infiltrations via ligand-receptor (LR) interactions. However, the interactions, expression patterns, and clinical relevance of LR in the TME in ccRCC are insufficiently characterised. This study characterises the complex composition of the TME in ccRCC by analysing the single-cell sequencing (scRNA-seq) data of patients with ccRCC from the Gene expression omnibus database. On analysing the scRNA-seq data combined with the cancer genome atlas kidney renal clear cell carcinoma (TCGA-KIRC) dataset, 46 LR-pairs were identified that were significantly correlated and had prognostic values. Furthermore, a new molecular subtyping model was proposed based on these 46 LR-pairs. Molecular subtyping was performed in two ccRCC cohorts, revealing significant differences in prognosis between the subtypes of the two ccRCC cohorts. Different molecular subtypes exhibited different clinicopathological features, mutational, pathway, and immune signatures. Finally, the LR.score model that was constructed using ten essential LR-pairs that were identified based on LASSO Cox regression analysis revealed that the model could accurately predict the prognosis of patients with ccRCC. In addition, the differential expression of ten LR-pairs in tumour and normal cell lines was identified. Further functional experiments showed that CX3CL1 can exert anti-tumorigenic role in ccRCC cell line. Altogether, the effects of immunotherapy were connected to LR.scores, indicating that potential medications targeting these LR-pairs could contribute to the clinical benefit of immunotherapy. Therefore, this study identifies LR-pairs that could be effective biomarkers and predictors for molecular subtyping and immunotherapy effects in ccRCC. Targeting LR-pairs provides a new direction for immunotherapy regimens and prognostic evaluations in ccRCC.

A systematic pan-cancer analysis reveals the clinical prognosis and immunotherapy value of C-X3-C motif ligand 1 (CX3CL1)

“…Overexpression of CX3CL1 is typically associated with improved prognosis because of its ability to modulate the body’s immune response. Liu et al discovered that CX3CL1 might exert an anti-tumorigenic effect on the KIRC cells line, hence contributing to the clinical benefit ( Liu et al, 2022 ). Tsaur and his colleagues demonstrated that renal cells carcinoma of the chromophobe subtype had considerably reduced CX3CL1 gene expression relative to normal tissue, and that CX3CR1 and C-reactive protein were positively correlated ( Tsaur et al, 2011 ).…”

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment

“…High EMT enrichment scores on bulk RNA sequencing are associated with worse disease specific survival in ccRCC 22 , and various EMT ligand-receptor pairs have been implicated. 23, 24,25 Prior spatial transcriptomic work using spot-based resolution has also identified EMT-rich tumor cells being associated with worse prognosis in the TCGA cohort. 26 Still, specific ligand-receptor pairs from the EMT pathway were not elucidated in these studies.…”

CX3CL1 promotes cell sensitivity to ferroptosis and is associated with the tumor microenvironment in clear cell renal cell carcinoma

“…So far, various studies have provided conflicting results regarding the role of CX3CL1 in anti-tumor immunity. Recent studies have suggested that signaling through the ligand-receptor pair formed by CX3CL1 and its receptor CX3CR1 may improve the prognosis of ccRCC patients [ 38 ]. However, in another new clinical trial, the chemokine CX3CL1 was associated with shorter PFS in metastatic triple-negative breast cancer [ 39 ].…”