Development of a polyamine gene expression score for predicting prognosis and treatment response in clear cell renal cell carcinoma

Abstract

BackgroundsPolyamine metabolism (PM) is closely related to the tumor microenvironment (TME) and is involved in antitumor immunity. Clear cell renal cell carcinoma (ccRCC) not only has high immunogenicity but also has significant metabolic changes. However, the role of PM in the immune microenvironment of ccRCC remains unclear. This study aimed to reveal the prognostic value of PM-related genes (PMRGs) expression in ccRCC and their correlation with the TME.MethodsThe expression levels PMRGs in different cells were characterized with single-cell sequencing analysis. The PMRG expression pattern of 777 ccRCC patients was evaluated based on PMRGs. Unsupervised clustering analysis was used in identifying PMRG expression subtypes, and Lasso regression analysis was used in developing polyamine gene expression score (PGES), which was validated in external and internal data sets. The predictive value of PGES for immunotherapy was validated in the IMvigor210 cohort. Multiple algorithms were used in analyzing the correlation between PGES and immune cells. The sensitivity of PGES to chemotherapeutic drugs was analyzed with the “pRRophetic” package. We validated the genes that develop PGES in tissue samples. Finally, weighted gene co-expression network analysis was used in identifying the key PMRGs closely related to ccRCC, and cell function experiments were carried out.ResultsPMRGs were abundantly expressed on tumor cells, and PMRG expression was active in CD8+ T cells and fibroblasts. We identified three PMRG expression subtypes. Cancer and immune related pathways were active in PMRG expression cluster A, which had better prognosis. PGES exhibited excellent predictive value. The high-PGES group was characterized by high immune cell infiltration, high expression of T cell depletion markers, high tumor mutation burden and tumor immune dysfunction and exclusion, was insensitive to immunotherapy but sensitive to sunitinib, temsirolimus, and rapamycin, and had poor prognosis. Spermidine synthetase (SRM) has been identified as a key gene and is highly expressed in ccRCC at RNA and protein levels. SRM knockdown can inhibit ccRCC cell proliferation, migration, and invasion.ConclusionsWe revealed the biological characteristics of PMRG expression subtypes and developed PGES to accurately predict the prognosis of patients and response to immunotherapy.

Polyamines: the pivotal amines in influencing the tumor microenvironment

“…High levels of polyamine metabolism are also a marker for poorer prognosis in clear cell renal carcinoma. Surprisingly, Chen et al found that clear cell renal carcinoma patients with high expression of polyamine-related genes show an increase in immune infiltrate but a poorer response to immunotherapies [ 177 ]. The authors discovered that high expression of polyamine-related genes was associated with increased Tregs in the TME and increased expression of T-cell exhaustion markers such as CTLA-4, TIGIT, and LAG3, indicating that while there may be more immune infiltrate in the TME, they may not be sensitive to immunotherapy due to immune escape [ 177 ].…”

“…Surprisingly, Chen et al found that clear cell renal carcinoma patients with high expression of polyamine-related genes show an increase in immune infiltrate but a poorer response to immunotherapies [ 177 ]. The authors discovered that high expression of polyamine-related genes was associated with increased Tregs in the TME and increased expression of T-cell exhaustion markers such as CTLA-4, TIGIT, and LAG3, indicating that while there may be more immune infiltrate in the TME, they may not be sensitive to immunotherapy due to immune escape [ 177 ]. It is important to note that while gene expression of polyamine metabolism-related genes may be of prognostic value, it is not necessarily informative of polyamine levels in the tumor.…”

Identification and Validation of eRNA as a Prognostic Indicator for Cervical Cancer

“…Given that chemotherapy is still used as adjuvant therapy in the clinic, we conducted a search for potential drugs that can increase drug sensitivity in high-risk patients. This increase in sensitivity is due to changes in eRNA expression [24,25]. To evaluate chemotherapeutic sensitivity in the TCGA high-and low-risk sets, we utilized the "oncoPredict" R package.…”

The effect of telomeres in cervical cancer

“…Afterwards, we visualized the variations in immune cells between cervical cancer and control samples using the packages limma, reshape2, and ggpubr. The main function of these packs is to correlate immune cells with their genes 15 .…”