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

Ilaria Grazia Zizzari1, Chiara Napoletano2, Andrea Botticelli3

  • 1Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy. ilaria.zizzari@uniroma1.it.

Cancer Immunology Research
|April 28, 2018
PubMed

Insights

Pazopanib, a tyrosine kinase inhibitor, enhances dendritic cell function and T-cell proliferation in metastatic renal cell carcinoma (mRCC) patients. This suggests pazopanib may improve responses when combined with immune checkpoint inhibitors.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Metastatic renal cell carcinoma (mRCC) treatment has improved with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs).
  • Understanding TKI immunomodulatory effects and patient selection is crucial for optimizing immunotherapy in mRCC.

Purpose of the Study:

  • To investigate the impact of the TKI pazopanib on dendritic cell (DC) performance and immune priming in mRCC.
  • To explore the underlying mechanisms of pazopanib's effects on DCs and T-cells.

Main Methods:

  • Assessed DC differentiation, maturation markers (HLA-DR, CD40, CCR7), IL10 production, endocytosis, and T-cell proliferation.
  • Investigated the effect of pazopanib on the Erk/β-catenin pathway and PD-L1 expression.
  • Confirmed findings in DCs from mRCC patients undergoing pazopanib treatment.

Main Results:

  • Pazopanib improved DC differentiation and performance, increasing maturation markers and T-cell proliferation while decreasing IL10 and endocytosis.
  • Pazopanib downregulated PD-L1 expression and inhibited the Erk/β-catenin pathway.
  • Pazopanib enhanced circulating CD4+ T-cells expressing CD137 (4-1BB) in treated mRCC patients.

Conclusions:

  • Pazopanib exhibits immunomodulatory effects that enhance DC activation and T-cell responses.
  • The Erk/β-catenin pathway may mediate pazopanib-induced DC activation.
  • Pazopanib holds potential for combination therapy with ICIs to improve outcomes in mRCC.

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