Comprehensive Multi-Omics Identification of Interferon-γ Response Characteristics Reveals That RBCK1 Regulates the Immunosuppressive Microenvironment of Renal Cell Carcinoma

Abstract

Interferon-gamma (IFN-γ) has a complex role in modulating the tumor microenvironment (TME) during renal cell carcinoma (RCC) development. To define the role of IFN-γ response genes in RCC progression, we characterized the differential gene expression, prognostic implications, and DNA variation profiles of selected IFN-γ response signatures, which exhibited a significant hazard ratio for the overall survival (OS) and progression-free survival (PFS) of papillary, chromophobia, and clear cell RCC (ccRCC) patients (n = 944). Prognostic nomograms were constructed to predict the outcomes for ccRCC patients, highlighting the prognostic implications of RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1). Interestingly, large-scale pan-cancer samples (n = 12,521) and three single-cell RNA datasets revealed that RBCK1 showed markedly differential expression between cancer and normal tissues and significantly correlated with tumor-infiltrating immune cells, tumor purity, and immune checkpoint molecules, such as PD-L1, CTLA-4, LAG-3, and TIGIT in pan-cancer samples. Notably, the TIDE score was significantly higher in the RBCK1high group compared with the RBCK1low group in both ccRCC and RCC cohorts. Besides, immunohistochemistry staining showed significantly elevated RBCK1 expression in tumors (n = 50) compared with kidney samples (n = 40) from a real-world cohort, Fudan University Shanghai Cancer Center (FUSCC, Shanghai). After RBCK1 expression was confirmed in ccRCC, we found a significantly decreased number of infiltrating CD4+ T cells, CD4+ FOXP3+ Treg cells, M1 macrophages, and CD56bight/dim NK cells in the immune-cold RBCK1high group. In addition to the distinct heterogeneous immune microenvironment, the increased expression of RBCK1 predicted a prominently worse prognosis than the RBCK1low group for 232 ccRCC patients in the FUSCC proteomic cohort. Furthermore, after transfected with siRNA in human ccRCC cells, extraordinarily decreased cell proliferation, migration capacities, and prominently elevated apoptosis tumor cell proportion were found in the siRNA groups compared with the negative control group. In conclusion, this study identified IFN-γ response clusters, which might be used to improve the prognostic accuracy of immune contexture in the ccRCC microenvironment. Immune-cold RBCK1high patients have pro-tumorigenic immune infiltration and significantly worse outcomes than RBCK1low patients based on results from multi-omics to real-world data. Our discovery of novel independent prognostic indicators for RCC highlights the association between tumor alterations and immune phenotype.

Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

“…Increasing evidence suggests that the malignant behaviors and treatment resistance of cancers are heavily governed by the crosstalk between the TME and tumor cells 28 . Chemokines are crucial in modulating the activity and tolerance status of tumors, as well as the abundance and cellular differentiation of TILs involved in pro-and anti-tumorigenic immune activities [29][30][31][32] . Previous studies found high CCL5 expression in PBRM1 MUT ccRCC patients that exhibited poor clinical outcomes and increased mast cell infiltration 33 .…”

Immunogenomic Characteristics of Cell-Death-Associated Genes with Prognostic Implications in Bladder Cancer

“…Most tumors arise and develop under strong evolutionary pressures imposed by factors such as nutrition, metabolism, immunity, and therapy. These pressures promote the diversification of the tumor microenvironment, ultimately leading to a degree of inherent tumor heterogeneity that enables disease progression and drug resistance ( 45 ). To validate the immunophenotype, 42 patients with BCa receiving immunotherapies were enrolled from the FUSCC cohort, and expression patterns of three CDI hub genes (DRD5, SCL2A14, and IGF1) were detected using IHC staining analysis.…”

RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31

“…Moreover, previous studies have revealed a markedly negative correlation between RNF31 expression and survival time in a variety of cancer types, such as prostate [ 19 ], breast [ 21 ], gastric [ 16 ], and colon cancers [ 20 ]. In addition, RBCK1 is highly expressed in pulmonary adenocarcinoma [ 23 ], breast cancer [ 24 ], colon cancer [ 25 ], and renal cell carcinoma [ 26 , 27 ]. These observations agree with our findings, suggesting that RNF31 and RBCK1 may be used as prognostic markers in patients with HCC.…”

“…RBCK1 is an RBR E3 ligase [ 22 ]. RBCK1 has been reported to be overexpressed in lung adenocarcinoma [ 23 ], breast cancer [ 24 ], colorectal cancer [ 25 ], and renal cell carcinoma [ 26 , 27 ], where high RBCK1 expression correlates with an unfavorable prognosis. RBCK1 promotes tumor progression through several mechanisms.…”