The treatment of renal cell carcinoma (RCC) has changed greatly over the past 15 years. Progress in the surgical management of the primary tumor and increased understanding of the molecular biology and genomics of the disease have led to the development of new therapeutic agents. The management of the primary tumor has changed owing to the realization that clean margins around the primary lesion are sufficient to prevent local recurrence, as well as the development of more sophisticated tools and techniques that increase the safety of partial nephrectomy. The management of advanced disease has altered even more dramatically as a result of new agents that target the tumor vasculature or that attenuate the activation of intracellular oncogenic pathways. This review summarizes data from prospective randomized phase III studies on the surgical management and systemic treatment of RCC, and provides an up to date summary of the histology, genomics, staging, and prognosis of RCC. It describes the management of the primary tumor and offers an overview of systemic agents that form the mainstay of treatment for advanced disease. The review concludes with an introduction to the exciting new class of immunomodulatory agents that are currently in clinical trials and may form the basis of a new therapeutic approach for patients with advanced RCC.

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy–treated RCC primary tumors showed increased infiltration of CD4⁺ and CD8⁺ T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4⁺FOXP3⁺ regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1–blocking agents. Cancer Immunol Res; 3(9); 1017–29. ©2015 AACR.

Mechanistic insights into kidney cancer: Many clear cell renal cell carcinomas (ccRCCs) have alterations to the gene encoding the von Hippel-Lindau protein (VHL). VHL is a ubiquitin ligase that degrades target proteins when they are prolyl-hydroxylated. Zhang et al. performed a genome-wide search for VHL target (see the Perspective by Sanchez and Simon). They identified ZHX2, a protein with structural motifs that indicate DNA binding. ZHX2 has been implicated in tumor suppression. Loss of ZHX2 inhibited signaling through the transcription factor NF-κB, and ZHX2 bound to many NF-κB target genes. Depletion of ZHX2 slowed growth of ccRCC cells in vitro and in a mouse model. Science , this issue p. 290 ; see also p. 226