Fig. 6

Immunomodulatory effects of regorafenib via inhibition of CSF1R. Untreated CRC tumors release CCL2 into the circulation, which induces an increase of CD115^hi immune cells in the blood, presumably mostly monocytes mobilized from bone marrow precursors. This is accompanied by a rise in F4/80^hi TAMs, which also express CD115, although at a lower level compared with the CD115^hi cells in the blood, and which mediates their survival, proliferation, and differentiation into the protumorigenic M2 subtype. In tumor-bearing mice treated with REG, inhibition of CSF1R results in a concerted and significant reduction in the number of CD115^hi cells in the blood and F4/80^hi cells in the tumor. Residual TAMs by default become the antitumorigenic M1 subtype. This contributes to tumor growth inhibition, together with other effects mediated by the inhibition of multiple other kinases by REG. Complete tumor remission by REG may be prevented by upregulation of tumor-trophic CCL2.