Fatty acids metabolism affects the therapeutic effect of anti-PD-1/PD-L1 in tumor immune microenvironment in clear cell renal cell carcinoma

Abstract

Background Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. Method RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan–Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. Results Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells’ malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. Conclusion The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.

CDKL3 shapes immunosuppressive tumor microenvironment and initiates autophagy in esophageal cancer

“…This suggests that high CDKL3 expression in ESCC cells may be associated with the activation of autophagy, which promotes macrophage M2 polarization. Lin et al also found that silencing IL4I1 in ccRCC cell lines (786-O, 769-P) could inhibit M2-like macrophage polarization by indirectly co-culturing with M0 macrophages (51). These results suggest that tumor cells with specific altered ge nes mi ght in fl uence immune cell infi ltration and functional polarization.…”

“…Lin et al. also found that silencing IL4I1 in ccRCC cell lines (786-O, 769-P) could inhibit M2-like macrophage polarization by indirectly co-culturing with M0 macrophages ( 51 ). These results suggest that tumor cells with specific altered genes might influence immune cell infiltration and functional polarization.…”

Fatty acid metabolism-related lncRNAs are potential biomarkers for survival prediction in clear cell renal cell carcinoma

“…[47,48] After conducting extensive investigations on metabolic reprogramming, researchers have come to recognize the significance of FA metabolism in ccRCC. [10,11,13,19] Lin et al [17] developed twenty mRNA signatures associated to fatty acid metabolism in the TCGA dataset. These signatures showed a high prediction ability, as indicated by time-dependent ROC and KM survival analysis.…”

“…[10,11] Abnormal fatty acid (FA) metabolism has been detected in various cancer forms, such as RCC, breast cancer, gastric cancer, prostate cancer, and lung cancer. [12–18] Notably, the TCGA analysis of ccRCC revealed that metabolic changes play a crucial role in the evolution of ccRCC. [14,19,20] A study and its subsequent analysis revealed a correlation between poorer survival of ccRCC patients and the increased expression of genes related to the pentose phosphate pathway and fatty acid synthesis pathway, as well as the decreased expression of genes related to the TCA cycle.…”

Novel application of the ferroptosis-related genes risk model associated with disulfidptosis in hepatocellular carcinoma prognosis and immune infiltration

“…First, we have previously performed univariate Cox regression analysis to screen out DE-DRG-FRG associated with OS as model candidate genes. Subsequently, to avoid collinearity and overfitting, the least absolute shrinkage and selection operator (LASSO) were conducted with the R “glmnet” package ( Xu et al, 2023 ) to complete the compression of the coefficients and eliminate genes with zero coefficient ( Lin et al, 2023 ). Finally, we chose the genes with non-zero coefficients to carry on multivariate Cox regression analysis, and the regression coefficients of each gene were obtained.…”