No abstract

The management of advanced renal cell carcinoma (RCC) has been transformed by the development of immune checkpoint inhibitors (ICIs), but still most RCC patients do not receive durable clinical benefit. Importantly, RCC differs substantially from other immunotherapyresponsive solid tumors -it has a modest mutation burden, and paradoxically, high CD8 + T cell infiltration has been associated with a worse prognosis. Building on the successes of inhibitory antibodies targeting the PD-1 and CTLA-4 axes, multiple innovative immunotherapies are now in clinical development for the treatment of RCC, including new ICIs, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cellular therapies, and therapeutic vaccinations. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a RCC-specific framework for understanding the necessary immunotherapeutic interventions that underlie an effective anti-tumor immune response. Here, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful anti-RCC immune response, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyze encouraging targets within the RCC microenvironment, and review the landscape of antigen-directed therapies in this disease.