Ricerc@Sapienza

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting,
for example, the VEGF receptors in tumors and have
improved outcomes for patients with metastatic renal cell carcinoma
(mRCC). Immune checkpoint inhibitors (ICIs) have
also been proposed for treatment of mRCC with encouraging
results. A better understanding of the activity of immune cells in
mRCC, the immunomodulatory effects of TKIs, and the characteristics
defining patients most likely to benefit from various
therapies will help optimize immunotherapeutic approaches. In
this study, we investigated the influence of the TKI pazopanib on
dendritic cell (DC) performance and immune priming. Pazopanib
improved DC differentiation and performance by promoting
upregulation of thematuration markers HLA-DR, CD40 and CCR7; decreasing IL10 production and endocytosis; and
increasing T-cell proliferation. PD-L1 expression was also downregulated.
Our results demonstrate that pazopanib inhibits the
Erk/b-catenin pathway, suggesting this pathway might be
involved in increased DC activation. Similar results were confirmed
in DCs differentiated from mRCC patients during pazopanib
treatment. In treated patients pazopanib appeared to
enhance a circulating CD4þ T-cell population that expresses
CD137 (4-1BB). These results suggest that a potentially
exploitable immunomodulatory effect induced by pazopanib
could improve responses of patients with mRCC in customized
protocols combining TKIs with ICI immunotherapy