Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib

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.

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma

“…Various targets of CZ are associated with immunosuppression, thus allowing it to directly immunomodulate the tumor microenvironment, increase cytotoxic T cell activation/infiltration, and induce susceptibility of tumor cells to cytotoxic T cell-mediated tumor cell killing, differentiating itself from other VEGF-targeting TKIs [ 26 , 37 , 39 , 41 , 43 , 44 , 67 , 74 ]. In particular, TAM kinases such as AXL and MET promote immunosuppressive phenotypes in tumor-associated immunosuppressive cells (including regulatory T cells, myeloid-derived suppressor cells, and tumor-activated macrophages) [ 37 ], which in turn contribute to the resistance against immune checkpoint inhibitors [ 37 , 41 ].…”

“…In particular, TAM kinases such as AXL and MET promote immunosuppressive phenotypes in tumor-associated immunosuppressive cells (including regulatory T cells, myeloid-derived suppressor cells, and tumor-activated macrophages) [ 37 ], which in turn contribute to the resistance against immune checkpoint inhibitors [ 37 , 41 ]. The combined AXL, VEGFR, and MET inhibition appears to be a relatively unique characteristic of CZ; hence, it is unsurprising that CZ monotherapy promotes unique immunomodulatory effects on innate and adaptive anticancer immunity in advanced RCC [ 26 , 37 , 39 , 41 , 43 , 44 , 67 , 74 ]. Interestingly, CZ-PLGA-NPs treatment significantly promoted the infiltration of cytotoxic CD8 + T cells into the metastatic lung bed ( Figure 8 B), suggesting that CZ-PLGA-NPs may mechanistically support the infiltration of cytotoxic CD8 + T into the tumor microenvironment, enhancing anti-tumor T cell immunity and contributing to the observed reduction in RCC lung metastasis growth.…”

“…RCC management has advanced significantly with the advent of newer generation TKIs, such as cabozantinib (CZ), that are effective in the first-line setting for intermediate- or poor-risk metastatic RCC, with significant clinical benefits in the progression-free survival and overall response rate [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. CZ is an oral, potent multi-target TKI that targets the VEGF receptor (VEGFR)-2 and several other receptor tyrosine kinases (RTKs), including the hepatocyte growth factor receptor (MET), the TAM (TYRO-3, AXL, and MER) family of receptor kinases, the ROS proto-oncogene 1, the c-kit proto-oncogene product, the Fms-related receptor tyrosine kinase 3, the tropomyosin receptor kinase B, the angiopoietin-1 receptor, and the RET proto-oncogene [ 34 , 35 , 39 , 41 , 42 , 44 ].…”

Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma

“…Thus far, it has become clear that most therapeutic interventions aimed to dampen tumor growth, promote anti-tumor response as a bystander effect by reducing immune suppression and/or enhancing antigen presentation and eliciting T cell responses [ 172 , 173 , 174 ]. This indirect immune modulation contributes to the overall clinical benefit induced by the therapy [ 175 ].…”

Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

“… 20 , 21 In addition, a recent in vitro study showed that cabozantinib triggered immunogenic cell death in prostate cancer cells and directly modulated dendritic cells, suggesting an immunostimulatory role. 22 …”