Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib

Fabio Scirocchi; Chiara Napoletano; Angelica Pace; Hassan Rahimi Koshkaki; Alessandra Di Filippo; Ilaria Grazia Zizzari; Marianna Nuti; Aurelia Rughetti

doi:10.3389/fonc.2021.755433

Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib

Front Oncol. 2021 Oct 20:11:755433. doi: 10.3389/fonc.2021.755433. eCollection 2021.

Authors

Fabio Scirocchi¹, Chiara Napoletano¹, Angelica Pace¹, Hassan Rahimi Koshkaki¹, Alessandra Di Filippo¹, Ilaria Grazia Zizzari¹, Marianna Nuti¹, Aurelia Rughetti¹

Affiliation

¹ Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Abstract

Cabozantinib (XL-184) is a multitarget tyrosine kinase inhibitor (TKI) targeting receptor tyrosine kinases (RTKs) involved in oncogenesis and angiogenesis. It is currently the standard therapy for medullary thyroid cancer (MTC), metastatic renal cell carcinoma (mRCC), and hepatocellular carcinoma (HCC). Combination of Cabozantinib with immunotherapy is now a standard treatment in metastatic renal cancer, and its efficacy is being tested in ongoing clinical trial in prostate cancer patients. Here, we report that Cabozantinib may exert an immunostimulatory role by inducing immunogenic stress of prostate cancer cells and directly modulating dendritic cells (DCs). Cabozantinib treatment arrested the cell cycle and triggered immunogenic cell death (ICD) in prostate cancer cells in vitro. Cabozantinib had a direct effect on DCs by the down-modulation of β-catenin and change in migratory and costimulatory phenotype of the DCs. These results may suggest possible immunomodulatory effects induced by Cabozantinib that could be exploited to optimize patient-tailored immunotherapeutic treatments.

Keywords: Cabozantinib; HMGB1; TKI (tyrosine kinase inhibitors); dendritic cell (DC); extracellular vesicle (EV); immunogenic cell death (ICD); immunotherapy; prostate cancer.