Table 1.
Pro- and antitumor effects of multiple tyrosine kinase inhibitors mediated via TAMs
| Tyrosine Kinase Inhibitor | Molecular Target(s) | Investigation Setting | TAM Effect | Ref. |
|---|---|---|---|---|
| Sunitinib | VEGFR1-3, PDGFR-α/β, c-Kit, CSF-1R, Flt-3 | Inflammatory corneal lymphangiogenesis | Decreases recruitment of F4/80+ macrophages and activity of their secreted factors such as VEGFA, VEGFC | 77 |
| Human renal cell carcinoma | Inhibits myeloid cell proliferation. However, GM-CSF induced resistance of sunitinib was found in intratumor myeloid cells | 105 | ||
| Human recurrent glioblastoma | More severe hypoxia was induced, which increased macrophage infiltration | 80 | ||
| Gastrointestinal stroma tumor (GIST) | Promotes M1 macrophage secretion of IL-10 in vitro | 106 | ||
| Human primary breast cancer | Synergizes with α-GITR to induce antitumor macrophages via inhibition of STAT3 activity | 74 | ||
| Sorafenib | VEGFR1-3, PDGFR-β, Raf-1, B-Raf, CSF-1R | Hepatocellular carcinoma | Converts alternative TAMs to M1-like TAMs and increases secretion of pro-inflammatory cytokines | 70 |
| Triggers macrophage- mediated cytotoxic NK cell activation | ||||
| Murine breast cancer | Increases IL-12 and suppression of IL-10 levels in macrophage | 71 | ||
| Human peripheral CD14+ monocyte derived macrophage | Induces apoptosis and autophagy in macrophages | 108 | ||
| Mouse model for metastatic liver cancer model | Increases peripheral and F4/80+ and CD11b+ macrophage recruitment and infiltration in cancer tissues | 109 | ||
| Mouse breast cancer model and pancreatic β-cell tumor model | Increases angiogenic and immunosuppressive molecules. Can be blocked by PI3K inhibitor IPI145 | 81 | ||
| Classical Hodgkin’s lymphoma | Blocks CSF-1R activity | 107 | ||
| Imatinib | c-Kit | Murine GIST model; human GIST | Shifts TAM into a more M2-like protumor phenotype macrophage | 110 |
| Promotes M1 macrophage secretion of IL-10 in vitro | 106 | |||
| Cediranib | VEGFR1-3 | Alveolar soft part sarcoma (ASPS) | Increases CD68+ and M2-like TAMs and increases CD163, Tie-2, and CCL2 mRNA levels | 111 |
| Transiently decreases macrophage infiltration. Increases plasma VEGFA levels and CXCR4+ CD45+ immune cells. | ||||
| Murine glioma xenograft model | Increases phosphorylation of STAT3 in macrophages. In combination with AZD1480 JAK2 inhibitor, decreases phospho- STAT3+ macrophages | 89 | ||
| Axitinib | VEGFR1-3, PDGFR-β and c-Kit | Murine glioma xenograft model | Inhibits metronomic cyclophosphamide activated antitumor innate immunity and shifts TAM into an M2-like phenotype | 91 |
| Erlotinib | EGFR, ErbB1 | Human U937 cell line induced macrophage | Inhibits monocyte-macrophage differentiation and proliferation | 76 |
| Non small cell lung cancer | Administration of erlotinib induces macrophage and other mononuclear cell infiltration into skin | 112 | ||
| Dasatinib | EGFR, ErbB1 | Murine bone marrow– derived macrophage; RAW264.7 cell line | Induces macrophages with anti-inflammatory function by increasing IL-10 production and suppressing TNF- α and IL-12p40 | 113 |
| Bosutinib | ||||
| PLX3397 | c-Kit, c-Fms inhibitor | Malignant peripheral nerve sheath tumor | Depleting Iba-1+ macrophages combined with rapamycin leads to more severe depletion of TAMs | 78 |
| Recurrent glioblastoma | Depletes CD11b+ cells and potentiates the response of the intracranial tumors to irradiation | 79 | ||
Abbreviations: EGFR, epidermal growth factor receptor; GITR, glucocorticoid-induced tumor necrosis factor (TNF) receptor; NK, natural killer; PI3K, phosphatidylinositol-3 kinase.