Table 2.
General working mechanism of approved targeted therapies and their effect on immune cells
| Drug | General working mechanism | Effect on the immune system | Refs. |
|---|---|---|---|
| Sunitinib | Blocks multiple tumor-associated tyrosine kinases, including VEGFR and PDGFR and c-kit tyrosine kinases | Immunostimulatory: Blocks STAT3 Decreases numbers and effectiveness of MDSCs and Treg cells Stimulates T cell priming by DCs Blocks VEGF signaling Reduces the expression of co-inhibitory molecules PD-1 and CTLA-4 | 85–89,92 |
| Sorafenib | Blocks multiple tumor-associated tyrosine kinases, including VEGFR and PDGFR and c-kit tyrosine kinases | Immunostimulatory: reduces Tregs, decreases NK cell inhibition, stimulates pro-inflammatory activity of macrophages Immunosuppressive: prevents upregulation of co-stimulatory molecules, reduces T cell proliferation, lowers cytokine secretion by DCs | 92,94–96 |
| Pazopanib | Blocks multiple tumor-associated tyrosine kinases, including VEGFR and PDGFR and c-kit tyrosine kinases | Unknown | 97 |
| Axitinib | Blocks multiple tumor-associated tyrosine kinases, including VEGFR and PDGFR and c-kit tyrosine kinases | Immunostimulatory: Reduces Tregs Reduces MDSCs | 98,99 |
| Temsirolimus and Everolimus = mTOR inhibitors | Blocks mTOR pathway | Immunostimulatory: enhances CD8+ T cell activation, enhance IFNγ production, enhance CD8+ T cell differentiation into memory T cells and decreases IDO expression Immunosuppressive: augments the responsiveness of Tregs to antigen | 85,102 |
| Bevacizumab | Blocks angiogenesis | Immunostimulatory: Blocks STAT3 Increases DC maturation Shifts DC differentiation toward mature DCs instead of MDSCs Increases DC priming of T cells | 85 |
Summary of the most important immunomodulatory properties of approved targeted agents in the treatment of renal cell carcinoma. The immunomodulatory properties of not all the targeted agents have been thoroughly studied already.
Abbreviations: VEGFR: vascular endothelial growth factor receptor, PDGFR platelet derived growth factor receptor, STAT3: signal transducer and activator of transcription 3, MDSCs: myeloid-derived suppressor cells, Tregs: regulatory T cells, DC: dendritic cell, VEGF: vascular endothelial growth factor, PD-1: programmed cell death protein-1, CTLA-4: cytotoxic T lymphocyte associated protein 4, NK cell: natural killer cell, mTOR: mammalian target of rapamycin, IFNγ: interferon γ, IDO: indoleamine-2,3-dioxygenase.