Metabolic classifications of renal cell carcinoma reveal intrinsic connections with clinical and immune characteristics

Abstract

Background Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative. Methods Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity. Results Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8+ T cells. Conclusions Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer

“…Current studies have reported that ACAA2 is a prognostic factor in IDH mutation lower‐grade glioma 29 . The downregulation of ACAA2 promotes the progression of renal cell carcinoma and liver cancer 30,31 . It is reported that ACAA2, as a BNIP3 binding partner, provides a possible link between fatty acid metabolism and apoptosis in human hepatoma HepG2 cells and U2OS osteosarcoma cells 32 .…”

“…ACAA2 is a ligand‐dependent coactivator of thyroid hormone receptor β1 9 . In kidney cancer, ACAA2 is a tumor suppressor, associated with higher immune invasion and elevated PD‐1 expression in CD8+ T cells 10 . ACAA2 is a key factor linking tumor metabolism and tumor immunity 10 .…”

“…In kidney cancer, ACAA2 is a tumor suppressor, associated with higher immune invasion and elevated PD‐1 expression in CD8+ T cells 10 . ACAA2 is a key factor linking tumor metabolism and tumor immunity 10 . The expression level of ACAA2 is closely associated with poor prognosis in liver cancer and colorectal cancer 11,12 .…”

“…10 ACAA2 is a key factor linking tumor metabolism and tumor immunity. 10 The expression level of ACAA2 is closely associated with poor prognosis in liver cancer and colorectal cancer. 11,12 The above studies have shown that ACAA2 is closely related to gene expression, cell differentiation, cardiovascular development, tumor metabolism, tumor immunity, and the prognosis of tumor patients.…”

Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy

“…ACAT1 inhibition promoted the proliferation of CD8 + T cells and increased plasma membrane cholesterol levels. Together, anti-PD-1 antibodies and ACAT1 inhibitors have shown increased anti-tumor effectiveness [ 96 ]. Anti-PD-1 immunotherapy is not highly effective at treating nasopharyngeal cancer, despite the reality that CD8 + T cells are prevalent in the immune environment.…”