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 the maturation 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/β-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 CD4+ 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.

Zizzari, I. G., Napoletano, C., Botticelli, A., Caponnetto, S., Calabrò, F., Gelibter, A., Rughetti, A., Ruscito, I., Rahimi, H., Rossi, E., Schinzari, G., Marchetti, P., Nuti, M., TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway, <<CANCER IMMUNOLOGY RESEARCH>>, 2018; 6 (6): 711-722-722. [doi:10.1158/2326-6066.CIR-17-0594] [http://hdl.handle.net/10807/122910]

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Rossi, Ernesto;Schinzari, Giovanni;
2018

Abstract

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 the maturation 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/β-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 CD4+ 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.
eng
Zizzari, I. G., Napoletano, C., Botticelli, A., Caponnetto, S., Calabrò, F., Gelibter, A., Rughetti, A., Ruscito, I., Rahimi, H., Rossi, E., Schinzari, G., Marchetti, P., Nuti, M., TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway, <>, 2018; 6 (6): 711-722-722. [doi:10.1158/2326-6066.CIR-17-0594] [http://hdl.handle.net/10807/122910]
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