Kidney renal papillary cell carcinoma(KIRP) is a highly heterogeneous disease with a distinct clinicopathological and molecular profile compared to KIRC24. This means that some of the predictive markers or therapeutic strategies used for KIRC may not be appropriate for KIRP. Although the effect of IL15RA on KIRP has been confirmed in vitro, to our knowledge no high-throughput data have investigated the prognostic value and therapeutic potential of IL15RA in KIRP.
By exploring the expression of IL15RA in KIRP using the TCGA and GEO databases, we found that IL15RA was downregulated in KIRP samples compared to normal kidney samples. Interestingly, when we compared IL15RA expression in samples of different grades, types, and stages, we noticed that IL15RA was enriched in samples with higher grades or later stages. Furthermore, survival analysis and the nomogram of the TCGA database revealed that up-regulated IL15RA could predict a poor prognosis of KIRP. The survival analysis of the GEO database was not statistically significant probably because of the small sample size.
Chronic inflammation has been implicated as a major cause of tumor initiation and progression and is associated with various steps of oncogenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis25,26. Chronic inflammatory cells and their products are also important components of the TME, mediating immune responses, and generating pro- and anti-tumor effects27. For instance, IL-17, IL-6, and TNF are important cytokines of tumor progression in RCC28–30. These IL15-induced pro-inflammatory cytokines could be amplified by sIL-15Rα, which may promote tumor progression11. This is probably due to the longer half-life and greater bioavailability of the soluble complex sIL-15/IL-15Rα compared to monomeric sIL-1531. Our study also suggests that IL15RA expression is significantly positively associated with the immune and inflammatory response by analyzing the inflammation-related metagene, GO, and GSVA. In addition, the immune infiltration analysis in the present study demonstrated an up-regulation of IL15RA expression with an increased infiltration of macrophages M2, suggesting that IL15RA is mainly expressed on M2 macrophages in the TME of KIRP. However, a higher proportion of M2 macrophages in KIRP is associated with a worse prognosis32.
IL-15 is the ligand for IL15Rα, a cytokine with complex biological functions linking innate and adaptive immune responses in vivo33. Intrarenal IL-15 is produced by renal tubular and cortical cells and plays an important role in maintaining epithelial cell homeostasis, whereas renal cancer cells do not secrete IL-15, but express tmb-IL-15, which binds to IL15Rα to trigger pro-tumor effects13–15. Yuan et al. demonstrated that KIRP cell lines(ACHN) express tmb-IL-15 and showed that stimulation of RCC with exogenous IL-15Rα induced EMT and promoted cell migration and invasion 14. They then confirmed the mechanism of the process: tmbIL-15/sIL-15Rα complex first causes activation of the tyrosine kinase Src, which subsequently activates the PI3K/Akt pathway, and finally leads to EMT. This reverse signaling also leads to the phosphorylation of FAK, which is associated with increased migratory and invasive properties of RCC cells. These results are consistent with the enriched functions and KEGG pathways in our study. Moreover, we speculate that Rap1 may be an upstream signaling factor of Src based on the Rap1 signaling pathway and PI3K/Akt signaling pathway in the enriched KEGG pathways.
Moreover, we found that IL15RA has a strong positive relationship with these inhibitory immune checkpoints, particularly LAG3, which may lead to the suppression of the immune response to KIRP. LAG3 has been identified to be associated with poor outcomes in KIRP32. These findings may suggest that IL-15Rα in TME may represent a novel immune escape mechanism, while the inhibition of sIL-15Ra cleavage by ADAM-17 inhibitors may counteract this novel tumor escape mechanism and improve patient prognosis11.
However, there are several limitations of this study. First, the analysis is mainly based on the TCGA-KIRP cohort, some of the results lack validation by external independent cohorts due to asymmetric or missing data in the GEO database. More relevant clinical samples should be collected for KIRP research. Our research needs to be verified in a larger cohort of KIRP. Second, although partial results can be supported by previous studies, our conclusions were based on bioinformatics methods. Therefore, further experiments are needed to confirm the biological function of IL15RA in KIRP at both cellular and animal levels, which would improve the accuracy of this study.
In conclusion, in the current research, we found that IL15RA is downregulated in KIRP samples when compared with normal samples. However, among KIRP samples with different grades and stages, IL15RA is upregulated in relatively higher malignancy and later stages of KIRC. The survival curve and multivariate cox regression analysis indicated that upregulated IL15RA is an independent risk factor for poor prognosis of KIRC. A nomogram model was constructed and effectively predicted the survival rate of patients. Finally, IL15RA showed a strong positive relationship with these inhibitory immune checkpoints could represent a novel mechanism of immune escape, which may provide new sights for the potential of immunotherapy for KIRP.