**5. Role of immune system in kidney cancer and the future**

The role of immune system in kidney cancer is becoming more clear, whereas new findings that arise from clinical trials and identification of additional predictive biomarkers increase our understanding of the tumor microenvironment. Looking to the future based on the knowledge we have today, the perspective is a better understanding of immune system in tumor stroma as well as in various steps in cancer growth and metastasis.

Regarding RCC therapy, a promising option is the combination therapy based on targeted agents (inhibition of mTOR or VEGF pathways associated with immunotherapies) or immunotherapy + immunotherapy, which would overcome tumor resistance, as well as to restore functional immune system cancer surveillance and response. Currently, there are many clinical trials investigating combination therapy: nivolumab (anti-PD-1) + ipilimumab (anti-CTLA-4) [125], pembrolizumab (anti-PD-1) + ipilimumab (anti-CTLA-4) [126], pidilizumab (anti-PD-1) + vaccine (DC/RCC fusion cell vaccine) [127], atezolizumab (anti-PD-L1) + bevacizumab (anti-VEGF) [127], nivolumab (anti-PD-1) + bevacizumab (anti-VEGF) [128], pembrolizumab (anti-PD-1) + pazopanib (TKI) [129], nivolumab (anti-PD-1) + sunitinib [130].

Also, cell-based therapies have become interesting, which includes adoptive T-cell therapies such as tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR), and chimeric antigen T-cell (CAR-T) therapy [127].

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Other promising alternative of therapy for RCC is vaccine-based immunotherapy. AGS-003 is an autologous DC vaccine that is generated from host DCs in response to tumor mRNA [131], which is also to investigate in combination with sunitinib [132].

All these therapeutic investigations highlighted the importance of immune system in the future study about RCC. Information about immune system may be decisive for clinical decisions.
