Immune Checkpoint Inhibitor (ICI) Genes and Aging in Clear Cell Renal Cell Carcinoma (ccRCC): Clinical and Genomic Study

Abstract

Background: It is anticipated that there will be a large rise in the number of tumor diagnoses and mortality in those aged 65 and older over the course of upcoming decades. Immune checkpoint inhibitors, often known as ICIs, boost immune system activity by selectively targeting ICI genes. On the other hand, old age may be connected with unfavorable results. Methods: The Cancer Genome Atlas (TCGA) provided gene expression data from ccRCC tissue and key clinical variables. ICI gene databases were applied and verified using the GEO database. Results: We identified 14 ICI genes as risk gene signatures among 528 ccRCC patients using univariate and multivariable cox hazard models, and the elderly group was linked with poor survival. Then, by utilizing a new nomogram method, the TNFSF15 gene and age predicting values were estimated at one, three, and five years (85%, 81%, and 81%), respectively, and our age-related risk score was significant even after multivariable analysis (HR = 1.518, p = 0.009, CI = 1.1102.076). TNFSF15 gene expression was lower in elderly ccRCC patients (p = 0.0001). A negative connection between age and the TNFSF15 gene expression was discovered by correlation analysis (p = 0.0001). The verification of the gene by utilizing GEO (GSE167093) with 604 patients was obtained as external validation that showed significant differences in the TNFSF15 gene between young and elderly patients (p = 0.007). Additionally, the protein–protein interactions of the TNFSF15 gene with other ICI genes and aging-related genes was determined. In addition, the TNFSF15 expression was significantly correlated with pathological stages (p = 0.018). Furthermore, it was discovered that the biological processes of senescence, cellular senescence, the immune system, and many immune cell infiltration and immune function types are all closely tied. Conclusions: Along with the risk score evaluation, the ICI gene TNFSF15 was identified as a tumor suppressor gene related to inequalities in age survival and is associated with pathological stages and different immunity statuses. The aging responses of ccRCC patients and related gene expression need further investigation in order to identify potential therapeutic targets.

A novel nomogram and prognostic factor for metastatic renal cell carcinoma survival in the era of immune checkpoint inhibitors (ICIs)

“…For patients who had routine clear cell mRCC surgery, Sorbellini and colleagues developed a postoperative prognostic nomogram to aid the prediction of recurrence in patients with mRCC ( Kattan et al, 2001 ; Sorbellini et al, 2005 ; Zhang et al, 2018 ). In the treatment modalities, chemotherapy and surgery used as a monotherapy in mRCC improve survival relative to non-use, whereas, there is no change in radiation treatment, and that could be due to the significant impact of newly discovered targeted treatments in recent years ( Al-Danakh et al, 2022 ). In the study of chemotherapy and surgery usage, better survival significance were connected to therapeutic applications of both chemotherapy and surgery.…”

Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma

“…The cancer immunity cycle consists of seven steps from the release of tumor antigen to the lysis of tumor cells which requires the participation of immune system [ 83 ]. Most importantly, ICIs such as PD-1/PD-L1 and CTLA-4 inhibitors play a central role in the treatment of mRCC [ 84 , 85 ]. Immune evasion can occur at the steps of antigen presentation and activation, transportation of T cells and tumor infiltration and cytotoxic activity of T cells in TME; it can lead to primary or adaptive resistance in patients receiving immunotherapy [ 86 , 87 ].…”

Aging-related biomarker discovery in the era of immune checkpoint inhibitors for cancer patients

“…Finally, among the most altered genes in cancer with age are those of the immune microenvironment, which plays an important role in cancer prognosis and therapy. Hence, identifying and validating immune-related biomarkers associated with aging in cancer holds immense potential for clinical applications ( Figure 3 ) ( 19 , 28 , 58 , 59 ).…”

“…Further, TNFSF15 may simultaneously decrease the expression of VEGFR1 on the cell membrane and increase the synthesis of soluble VEGFR1, shifting the VEGF/VEGFR1 signaling pathway from promoting angiogenesis to inhibiting angiogenesis ( 200 ). Our team previously revealed that TNFSF15 gene expression was downregulated in clear cell renal cell carcinoma of geriatric with negative association between the TNFSF15 gene expression and age ( 59 ). Moreover, the protein-protein interaction between TNFSF15, other immune checkpoints, and proteins associated with aging demonstrates TNFSF15’s involvement in the aging mechanism.…”