Recently, the incidence and mortality of KIRC have risen sharply in the world . According to literature reports, there were about 63990 newly diagnosed renal cancer patients in 2017 in the United States , most of which were KIRC, placing a significant burden on affected patients, as well as their families and on the healthcare system as a whole. Although the improvement of basic research and clinical treatment in KIRC has improved the survival in KIRC patients in recent years, there are still 25%-30% of patients with tumor metastasis, and nearly one-third of patients have tumor recurrence . Patients with recurrent or metastatic KIRC have an extremely poor prognosis. The identification of reliable diagnostic and prognostics KIRC biomarkers would allow for better treatment planning and a significant improvement in overall patient survival. As such, it is of great significance to further understand the molecular mechanisms of occurrence, development and metastasis of KIRC and to explore new biomarkers.
Numerous experiments  have shown that stromal cells in the tumor microenvironment interact with tumor cells. Tumor cells in turn can directly influence the differentiation and activation of local mesenchymal cells through direct contact and via secreted factors, transforming them into tumor-associated mesenchymal cells which then secret proteins that can aid tumor progression. Given the importance of the tumor microenvironment to tumor progression, it represents a potentially ideal target worthy of study as a means of determining the prognosis of cancer patients based on tumor microenvironment-related gene expression. Therefore, in this study we assessed tumor microenvironment-related genes that were strongly correlated with KIRC patient OS, and conducted pathway and functional enrichment analyses of these genes, in addition to grouping them into protein-protein interaction networks. We found that several DEGs were significantly associated with KIRC patient prognosis, with all of these genes being associated with immune and inflammatory responses. These results thus highlighted to potential value of tumor microenvironment-related gene expression as a means of predicting clinical outcomes in individuals suffering from KIRC.
From the protein-protein interaction network in this study, IL-10 and CCL19 are highly interconnected nodes. IL-10 has currently been reported to be closely associated with proliferation, immune evasion, and prognosis in a variety of tumors, such as cervical cancer , lung cancer , colorectal cancer , noncardia gastric cancer  and so on. Wittke F, et al  also reported that IL-10 was an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma. Exactly how IL-10 functions in the development of renal clear cell tumors remains uncertain, with multiple mechanisms having been proposed to date. (1) Direct effects of cytokines. IL-10 is able to act directly on T cells, impairing Th1 cytokine production and enhancing Th2 cell differentiation, thus shifting the balance between Th1 and Th2 cells. (2) The inhibitory effect of cytokines on apoptosis. Some cytokines, such as IL-10, IL-6 and GM-CSF, could inhibit apoptosis and further promote KIRC development. (3) Counteraction of KIRC tumor tissue. KIRC cells are able to induce monocytes to produce IL-10 and PGE2, while PGE2 can induce monocytes and macrophages to produce IL-10, which in turn causes a Th1-Th2 shift by regulating the balance of Th1/Th2 cell subsets, thus inducing the development of KIRC. Meanwhile, as a class of small molecular secreted proteins that can chemotactic the directional movement of immune cells, CCL19 also plays a key role in inhibiting tumor proliferation, migration, and invasion . By studying a lung cancer model , Hillinger S, et al. reported that intratumoral injection of CCL19 significantly reduced the large size of tumors, and also found that the antitumor effect of CCL19 in the model was related to T cell-mediated immune responses. Lu J, et al  also found that CCL19 expression in colon cancer was significantly lower than that in adjacent normal tissues in clinical specimens, and patients with CCL19 positivity in tumors had a higher 5-year survival rate. CCL19 may play an anti-tumor effect through the following pathways [34–35]: (1) chemotactic T cells are involved in killing tumor cells; (2) inducing dendritic cells to enter tumor tissues; (3) directly binding to CCR7 receptor and activating the receptor pathway to inhibit tumor proliferation, invasion and metastasis. In addition, our results further suggested that CD79A, IGLL5, CD19, IGJ and TNFRSF17, which have not previously been linked with KIRC prognosis, could serve as potential biomarkers for KIRC, and further molecular studies are needed to confirm these predictions.
Several limitations of the study also exist. First, we recapitulated our findings in a single published dataset, which may impact the stability of the study and differ from the general population; a larger and multi-centric cohort study would be performed to replicate and validate our findings. Second, the mechanisms behind the prognostic values of the tumor microenvironment-related genes were not investigated; experimental studies should be performed to provide information about their functions with regards to KIRC.