Angiogenesis and Immunity in Renal Carcinoma: Can We Turn an Unhappy Relationship into a Happy Marriage?

Abstract

The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells’ (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC.

Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

“…Regarding the combination of ICI plus sunitinib, although the authors comprehensively demonstrated a direct impact of immune-and inflamed-infiltration (Teff High Myeloid High ) [73], it is still debated whether combining anti-angiogenic and immunological checkpoint inhibitors without proper selection, more than what would necessary constitutes a synergistic strategy [104]. Nonetheless, robust and compelling preclinical [20,104] and clinical [18] evidence supports the biological ecosystem dissection as the future driver of patient selection for choosing candidates among ICI/anti-angiogenic strategies: different biological RCC behaviors pinpoints the tight correlation existing by intermediate/high risk profile, tumor angiogenesis and indirect immune-tolerogenic milieu. Statistically powered prospective clinical studies are expected to be carried out, aiming at further validating the promising pioneering results [105].…”

“…From this perspective, the phenotypic deconvolution aiming to biomarkers identification and response prediction, can support customizing RCC treatment. From this standpoint, it is tempting to propose a combination of anti-angiogenic and immune-checkpoint inhibitors (ICI), especially when driven by compelling molecular signatures [19,20].…”

A Minimal PKPD Interaction Model for Evaluating Synergy Effects of Combined NSCLC Therapies

“…with x i expressed in mg/(mL•day). When combined with antiangiogenesis, immunotherapy increases the therapeutic effect with 25% [1,16,17,45] and up to 50% when combined with radiotherapy [15,34,35,46]. A linear combination of their synergic effect is considered for the tumor Et all and drug Ed all interactions:…”

“…It has been shown that combination therapy in cancer leads to synergic effects with improved outcome [ 1 , 2 ]. The SBRT (stereotactic body radiotherapy) is prevalent in lung cancer treatment as it is most patient friendly in terms of side effects, while proving to have excellent results [ 3 , 4 , 5 ].…”

<p>Immunotherapeutic Targets and Therapy for Renal Cell Carcinoma</p>

“…The TME is, in fact, a complex structure composed of different mediators involved in the cell signaling that may deeply influence sensitivity to immunotherapy. 26 In particular, the inactivation of VHL tumor suppressor gene, present in about 60% of RCC, results in an imbalance in pro-and anti-angiogenic factors. 27 Among the proangiogenic factors involved, the transcription factor hypoxia-inducible factor (HIF)-1α and VEGF induce the release of immunosuppressive factors, such as transforming growth factor β (TGF-β), PD-L1, and VEGF itself.…”