Molecular mechanisms and clinical relevance of endothelial cell cross-talk in clear cell renal cell carcinoma

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer in adults and stands out as one of the most vascularized and immune-infiltrated solid tumors. Overproduction of vascular endothelial growth factor A promotes uncontrolled growth of abnormal vessels and immunosuppression, and the tumor microenvironment (TME) has a prominent role in disease progression, drug targeting and drug response, and for patient outcome.

Methods: Studies of experimental models, large-scale omics approaches, and patient prognosis and therapy prediction, using gene expression signatures and tissue biomarker analysis, have been reviewed for enhanced understanding of the endothelium in ccRCC and the interplay with the surrounding TME.

Results: Preclinical and clinical studies have discovered molecular mechanisms of endothelial cross-talk of relevance for disease progression, patient prognosis, and therapy prediction. There is, however, a lack of representative ccRCC experimental models. Omics approaches have identified clinically relevant subsets of angiogenic and immune-infiltrated tumors with distinct molecular signatures and distinct endothelial cell and immune cell populations in patients.

Conclusions: Recent genetically engineered ccRCC mouse models together with emerging evidence from single cell RNA sequencing data open up for future validation studies, including multiplex imaging of ccRCC patient cohorts. These studies are of importance for therapy benefit and personalized treatment of ccRCC patients.

Keywords: Kidney cancer; clear cell renal cell carcinoma; endothelial cells; immune cells; tumor microenvironment; vasculature.

Figure 1

Tumor microenvironmental (TME) interplay in ccRCC; insights from preclinical and clinical research. CcRCC tumors are highly vascularized and infiltrated with immune cells. Endothelial cell (EC)-subsets have been identified, including ACKR1⁺ ECs distinct from VEGFR2⁺ ECs. The different ECs not only express unique markers, including PLVAP, but also share expression, including vWF. Paracrine signaling involves elevated VEGFA from tumor cells that activates PLCγ in ECs and enhances tumor vascular leakage and immunosuppression, important for patient survival. VEGFA also modulates the immune microenvironment by infiltration of exhausted T-cells, MDSCs, and tumor-associated macrophages (TAMs). TREM2⁺ TAMs promote tumor progression and worse outcome. Another example of paracrine cross-talk is oncostatin M secretion by Vhl-deficient cells, which binds EC OSMR to enhance metastatic spread in mice. The G-protein coupled receptor (GPCR) ELTD1 and the angiopoietin-2 ligand for the receptor tyrosine kinase Tie2 have been identified as predictive markers for sunitinib response in RCC patients, while the GPCR-coupled kinase PI3Kβ promotes sunitinib resistance and vascular permeability in experimental mouse models. Direct interactions of tumor cells and ECs involve the VEGFR2 co-receptor NRP1, which suppresses angiogenesis and tumor cell proliferation and promotes RCC patient survival. Systemic therapy for advanced ccRCC patients targets the TME and includes immune checkpoint blockade (ICB) in combination with antiangiogenic tyrosine kinase inhibitors (TKIs).