TK inhibitor pazopanib primes DCs by downregulation of the β-catenin pathway

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting,for example, the VEGF receptors in tumors and haveimproved outcomes for patients with metastatic renal cell carcinoma(mRCC). Immune checkpoint inhibitors (ICIs) havealso been proposed for treatment of mRCC with encouragingresults. A better understanding of the activity of immune cells inmRCC, the immunomodulatory effects of TKIs, and the characteristicsdefining patients most likely to benefit from varioustherapies will help optimize immunotherapeutic approaches. Inthis study, we investigated the influence of the TKI pazopanib ondendritic cell (DC) performance and immune priming. Pazopanibimproved DC differentiation and performance by promotingupregulation of thematuration markers HLA-DR, CD40 and CCR7; decreasing IL10 production and endocytosis; andincreasing T-cell proliferation. PD-L1 expression was also downregulated.Our results demonstrate that pazopanib inhibits theErk/b-catenin pathway, suggesting this pathway might beinvolved in increased DC activation. Similar results were confirmedin DCs differentiated from mRCC patients during pazopanibtreatment. In treated patients pazopanib appeared toenhance a circulating CD4þ T-cell population that expressesCD137 (4-1BB). These results suggest that a potentiallyexploitable immunomodulatory effect induced by pazopanibcould improve responses of patients with mRCC in customizedprotocols combining TKIs with ICI immunotherapy