Abstract Background IL-15 plays a vital role in enhancing NK cell- and T-cell-mediated antitumor immune responses; however, the direct effect of IL-15 on tumor cells has not been fully elucidated. Herein, we investigated the effect of IL-15 on lung adenocarcinoma cells. Methods Silencing and overexpression techniques were used to modify endogenous IL-15 expression in tumor cells. Transwell assays were used to assess tumor cell migration and invasion; a live-cell analysis system was used to evaluate cell motility; cellular morphological changes were quantified by confocal fluorescence microscopy; the molecular mechanisms underlying the effect of IL-15 on tumor cells were analyzed by western blotting; and RhoA and Cdc42 activities were evaluated by a pulldown assay. NCG and C57BL/6 mouse models were used to evaluate the functions of IL-15 in vivo. Results Cancer cell-intrinsic IL-15 promoted cell motility and migration in vitro and metastasis in vivo via activation of the AKT-mTORC1 pathway; however, exogenous IL-15 inhibited cell motility and migration via suppression of the RhoA-MLC2 axis. Mechanistic analysis revealed that both the intracellular and extracellular IL-15-mediated effects required the expression of IL-15Rα by tumor cells. Detailed analyses revealed that the IL-2/IL-15Rβ and IL-2Rγ chains were undetected in the complex formed by intracellular IL-15 and IL-15Rα. However, when exogenous IL-15 engaged tumor cells, a complex containing the IL-15Rα, IL-2/IL-15Rβ, and IL-2Rγ chains was formed, indicating that the differential actions of intracellular and extracellular IL-15 on tumor cells might be caused by their distinctive modes of IL-15 receptor engagement. Using a Lewis lung carcinoma (LLC) metastasis model, we showed that although IL-15 overexpression facilitated the lung metastasis of LLC cells, IL-15-overexpressing LLC tumors were more sensitive to anti-PD-L1 therapy than were IL-15-wild-type LLC tumors via an enhanced antitumor immune response, as evidenced by their increased CD8+ T-cell infiltration compared to that of their counterparts. Conclusions Cancer cell-intrinsic IL-15 and exogenous IL-15 differentially regulate cell motility and migration. Thus, cancer cell-intrinsic IL-15 acts as a double-edged sword in tumor progression. Additionally, high levels of IL-15 expressed by tumor cells might improve the responsiveness of tumors to immunotherapies.

SHC1 plays a crucial regulatory role in various tumors, but its significance in predicting prognosis and immune response in clear cell renal cell carcinoma (ccRCC) is yet to be determined. In this study, we conducted a bioinformatics analysis of SHC1 expression, prognosis, and immunological functions in ccRCC using multiple databases. The association between SHC1 and immune infiltration, immune escape, and immunotherapy in ccRCC was systematically established. In addition, we validated our results by western blot of tumor and adjacent-tumor samples from nine ccRCC patients, as well as three renal carcinoma cell lines compared to a normal renal cell line. Our analysis revealed that the mRNA expression level of SHC1 in ccRCC tissues is significantly higher than that in normal tissues. Consistently, western blot experiment showed ccRCC tissues and cell lines exhibit higher protein levels that normal tissues and cell lines. Importantly, patients with low expression of SHC1 demonstrated a higher survival rate, indicating that SHC1 could serve as an independent prognostic factor for predicting survival in ccRCC. Additionally, high expression of SHC1 was associated with increased severe immune cell infiltration, enhanced immune escape, and higher immunotherapy scores. Hence, SHC1 emerges as a novel and easily detectable biomarker for predicting clinical outcomes, immune escape, and immunotherapy response in patients with ccRCC.

Renal cell carcinoma (RCC) stands among the top 10 malignant neoplasms with the highest fatality rates. It exhibits pronounced heterogeneity and robust metastatic behavior. Patients with RCC may present with solitary or multiple metastatic lesions at various anatomical sites, and their prognoses are contingent upon the site of metastasis. When deliberating the optimal therapeutic approach for a patient, thorough evaluation of significant risk factors such as the feasibility of complete resection, the presence of oligometastases, and the patient’s functional and physical condition is imperative. Recognizing the nuanced differences in RCC metastasis to distinct organs proves advantageous in contemplating potential treatment modalities aimed at optimizing survival outcomes. Moreover, discerning the metastatic site holds promise for enhancing risk stratification in individuals with metastatic RCC. This review summarizes the recent data pertaining to the current status of different RCC metastatic sites and elucidates their role in informing clinical management strategies across diverse metastatic locales of RCC.

BACKGROUND:Cuproptosis is a novel cell death mechanism, and FDX1 is a key gene associated with cuproptosis. However, it is unclear whether FDX1 has prognostic and immunotherapeutic value for clear cell renal carcinoma (ccRCC).METHODS:Data on FDX1 expression in ccRCC were extracted from various databases and validated using qRT-PCR and western blotting. Moreover, the survival prognosis, clinical features, methylation, and biological functions of FDX1 were evaluated, and the tumor immune dysfunction and exclusion (TIDE) score was used to explore the immunotherapy response to FDX1 in ccRCC.RESULTS:The expression of FDX1 in ccRCC tissues was significantly lower than that in normal tissues, as validated by qRT-PCR and western blotting of patient samples (P < 0.01). Moreover, low FDX1 expression was related to shorter survival time and high immune activation, as indicated by alterations in the tumor mutational burden and tumor microenvironment, stronger immune cell infiltration and immunosuppression point expression, and a higher TIDE score.CONCLUSIONS:FDX1 could serve as a novel and accessible biomarker for predicting survival prognosis, tumor immune landscape, and immune responses in ccRCC.

Checkpoint kinase 2 (CHEK2) plays a crucial role in responding to DNA damage and is linked to diverse cancer types. However, its significance in the prediction of prognosis and impacts on the immune status of clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to identify the role of CHEK2 in prognosis and immune microenvironment of ccRCC. We analyzed transcriptome and clinicopathological data from the cancer genome atlas (TCGA) database and conducted functional enrichment analysis to explore molecular mechanisms. The relationship between CHEK2 and immune infiltration was evaluated, and drug sensitivity analysis was performed using the CellMiner database. The results showed that CHEK2 was an independent predictor of ccRCC prognosis and was closely associated with immune-related processes. Additionally, high expression of CHEK2 was linked to resistance to certain targeted drugs. These findings suggest that CHEK2 could serve as a biomarker for ccRCC, providing insights into tumor immune microenvironment alterations and immunotherapeutic response. Further investigation is needed to fully understand the potential of CHEK2 as a prognostic predictor and therapeutic target for ccRCC.

OBJECTIVE:Renal clear cell carcinoma (ccRCC) is the most common type of renal cancer. Here we aim to explore the prognosis and immunotherapeutic value of copper death-related gene Dihydrolipoamide S-acetyltransferase (DLAT) in ccRCC.METHODS:The mRNA and protein expressions and methylation level of DLAT, as well as the relation of DLAT to survival prognosis, clinical characteristics, biological function, and immune microenvironment and responses in patients with ccRCC were evaluated using multiple databases. In addition, 75 paired ccRCC tissue samples and 3 kinds of cell lines were tested for experimental validation.RESULTS:Bioinformatics analysis of multiple databases, qRT-PCR, and western blot verified that DLAT expression in ccRCC was lower than that in paracancerous tissues. Patients with low expression of DLAT had a lower survival rate, worse clinical prognosis, stronger immune cell infiltration and expression of immunosuppressive points, and higher tumor immune dysfunction and exclusion (TIDE) scores.CONCLUSIONS:DLAT was identified as an independent prognostic factor in ccRCC and was closely related to the prognosis and immune responses of patients with ccRCC.

BackgroundDespite numerous treatments available, clear cell renal cell carcinoma (ccRCC) remains a deadly and invasive cancer. Anoikis-related genes (ARGs) are essential regulators of tumor metastasis and development. However, the potential roles of ARGs in ccRCC remain unclear.MethodsBased on the TCGA-KIRC cohort and GeneCards database, we identified differentially expressed ARGs in ccRCC. Then a 4 ARGs risk model was created by Cox regression and LASSO. The Kaplan-Meier and receiver operating characteristic (ROC) curves were utilized to verify the predictive efficacy of the prognostic signature. Subsequently, the possible molecular mechanism of ARGs was investigated by functional enrichment analysis. To assess the immune infiltration, immune checkpoint genes, and immune function in various risk groups, single sample gene set enrichment (ssGSEA) algorithm was employed. Furthermore, the low-risk and high-risk groups were compared in terms of tumor mutation burden (TMB). Ultimately, we analyzed the protein expression of these four ARGs utilizing the western blot test.ResultsFour genes were utilized to create a risk signature that may predict prognosis, enabling the classification of KIRC patients into groups with low or high risk. The reliability of the signature was examined utilizing survival analysis and ROC analysis. According to the multivariate Cox regression result, the risk score was a reliable independent prognostic predictor for KIRC patients. The novel risk model could differentiate between KIRC patients with various clinical outcomes and represent KIRC’s specific immune status. An analysis of the correlation of TMB and risk score indicated a positive correlation between them, with high TMB being potentially linked to worse outcomes.ConclusionBased on our findings, the prognostic signature of ARGs may be employed as an independent prognostic factor for ccRCC patients. It may introduce alternative perspectives on prognosis evaluation and serve as a prominent reference for personalized and precise therapy in KIRC.

Background: m6A RNA methylation and tumor microenvironment (TME) have been reported to play important roles in the progression and prognosis of clear cell renal cell carcinoma (ccRCC). However, whether m6A RNA methylation regulators affect TME in ccRCC remains unknown. Thus, the current study is designed to comprehensively evaluate the effect of m6A RNA methylation regulators on TME in ccRCC. Methods: Transcriptome data of ccRCC was obtained from The Cancer Genome Atlas (TCGA) database. Consensus clustering analysis was conducted based on the expressions of m6A RNA methylation regulators. Survival differences were evaluated by Kaplan-Meier (K-M) analysis between the clusters. DESeq2 package was used to analyze the differentially expressed genes (DEGs) between the clusters. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were analyzed by ClusterProfiler R package. Immune, stromal and ESTIMATE scores were assessed by ESTIMATE algorithm. CIBERSORT algorithm was applied to evaluate immune infiltration. The expressions of human leukocyte antigen (HLA), immune checkpoint molecules, and Th1/IFNγ gene signature associated with TME were also compared between the clusters. TIDE algorithm and subclass mapping were used to analyze the clinical response of different clusters to PD-1 and CTLA-4 blockade. Results: The expressions of fifteen m6A regulators were significantly different between ccRCC and normal kidney tissues. Based on the expressions of those fifteen m6A regulators, two clusters were identified by consensus clustering, in which cluster 1 had better overall survival (OS). A total of 4,429 DEGs were found between the two clusters, and were enriched into immune-related biological processes. Further analysis of the two clusters’ TME showed that cluster 1 had lower immune and ESTIMATE scores, higher expressions of HLA and lower expressions of immune checkpoint molecules. Besides, immune infiltration and the expressions of Th1/IFNγ gene signature also have significant differences between two clusters. Conclusions: Our study revealed that m6A regulators were important participants in the development of ccRCC, with a close relationship with TME.

Therapeutic radiation can result in substantially different survival outcomes for patients with non-small cell lung cancer (NSCLC). Measures for identification of patients who can benefit most throughout radiotherapy remain limited. In this retrospective study, survival analysis was performed based on a discovery cohort from TCGA and a validation cohort from three independent hospitals. Tumor mutational burden (TMB) and chromosomal aneuploidy (ANE) were derived from the whole exome sequencing (WES) data from treatment-naïve tumors. Integrated risk scores were derived from TMB and ANE by a multivariate Cox proportional hazards model. TCGA reveal that TMB and ANE are associated positively and negatively, respectively, with survival throughout radiotherapy. Additionally, the synergistically predictive significance of these two genomic alterations, in differing responders and non-responders to radiotherapy is identified. These biomarkers may have clinical potential to improve personalized treatment management by rationally identifying highly likely responders to therapeutic radiation in patients with NSCLC.