Targeting the Tumor Microenvironment in Renal Cell Cancer Biology and Therapy

Abstract

Renal cell cancer (RCC) is a highly vascularized and immunogenic tumor type. The inhibition of vessel formation by anti-angiogenic therapies, as well as the stimulation of the immune system by immunotherapy has revolutionized the therapeutic landscape of RCC in recent years. Nevertheless, both therapies are associated with therapy resistance due to a highly dynamic, adaptive and heterogeneous tumor microenvironment (TME). The aim of this short review article is to provide an overview of the components of the RCC TME as well as to discuss their contribution to disease progression. In addition, we report on preclinical and clinical findings and how the different TME components can be modulated to impede treatment progression as well as to overcome therapy resistance to anti-angiogenic or immunomodulating therapy concepts. Furthermore, we discuss the predictive and prognostic role of the TME in RCC therapy. We also report on the concept of combinational targeting of anti-angiogenic therapies and immune checkpoint inhibitor therapy, also including the latest results of clinical studies discussed at recent oncological meetings. Finally, promising new therapeutic targets within the TME are mentioned.

Keywords: anti-angiogenesis; combination therapy; immunotherapy; renal cell cancer; therapy; tumor microenvironment (TME).

Figure 1

Schematic overview and recommendations from the current European Association of Urology 2018 guidelines for systemic treatment in mRCC. VEGF, vascular endothelial growth factor; IMDC, The International Metastatic Renal Cell Carcinoma Database Consortium.

Figure 2

Mechanistic interactions between VEGF-targeted anti-angiogenic therapy and checkpoint inhibitors in the systemic treatment of mRCC. Various VEGF-targeted and mTOR-targeted anti-angiogenic agents are currently approved in mRCC, inhibiting VEGF-A (bevacizumab); VEGFR1-3, FGFR1-4, PDGFR- α, c-kit, and RET-oncogene (lenvatinib); c-MET, AXL and RET, and VEGFR2 (cabozantinib); c-KIT, FGFR, PDGFR, and VEGFR (pazopanib); VEGFR1-3, c-KIT, and PDGFR (axitinib); VEGFR, PDGFR, and Raf family kinases (sorafenib); VEGFRs, PDGFRs, and RET (sunitinib). Everolimus and temsirolimus are specific inhibitors of mTOR and interfere with the synthesis of proteins that regulate proliferation, growth and survival of tumor cells. These agents are more selective for the mTORC1 protein complex, with very little impact on the mTORC2 complex. Nevertheless, increased tumor hypoxia during this anti-angiogenic therapy is the key player for developing TKI resistance, with consecutive HIF-α accumulation. Under hypoxia, PD-L1 upregulation was dependent on HIF-2α in RCC, being associated with simultaneous VEGF overexpression. Moreover, specimens from patients treated with anti-angiogenic therapy were associated with enhanced expression of PD-L1 (1). Thus, combined blockade of PD-L1 (avelumab or atezolizumab) or PD-1 (nivolumab or pembrolizumab) along with inhibition of the angiogenesis pathway is an innovative therapeutic concept in mRCC.