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. 2017 Jul 14;8:828. doi: 10.3389/fimmu.2017.00828

Figure 2.

Figure 2

Targeting tumor-associated macrophages (TAMs) with chemo- and immunotherapies. Different approaches have been proposed to modulate TAMs: (A) Depletion of TAMs: different kinds of treatments are available to destroy TAMs in tumor: toxins (Shigella flexneri attenuated strain or immunotoxin), liposome containing bisphosphonates [clodrolip, zoledronic acid (ZA) or ibandronate], and peptide modification to induce cytotoxic lymphocyte activation (e.g., legumain). Depletion of macrophages in tumor induced effective tumor regression in mouse and patients. (B) Inhibition of circulating monocyte recruitment into the tumor: two main recruitment effectors can be targeted to inhibit the recruitment of monocyte to the tumor site: CCL2/C–C chemokine receptor type 2 (CCR2) and colony-stimulating factor 1 (CSF-1)/CSF1-R. The use of monoclonal antibody against CCL2 (e.g., Carlumab) or CSF-1 inhibits tumor growth in mouse models and humans. Another way to prevent monocyte recruitment to the tumor site is the use of molecule targeting CCL2/CCR2 (e.g., bindarit) or CSF1/CSF1-R (e.g., BLZ945, PLX3397) pathways. (C) Blockade of M2 phenotype: the blockade of M2 phenotype can be achieved by targeting two main transcription factors: STAT3 (sorafenib, sunitinib, WP1066, and resveratrol) and STAT6 (4-HPR, leflunomid, TMX264, and AS1217499). All these inhibitors provide tumor regression and inhibited angiogenesis. (D) Enhanced activation of M1 macrophages or reprogramming of TAMs toward M1-like macrophages: TAM reprogramming into M1 macrophages can be achieved through the stimulation of STAT1 (IFNγ, vadimezan), AMPKα1 (metformin), or nuclear factor kappa B [toll-like receptor agonists such as imiquimod or CpG-ODNs; phosphoinositide 3-kinase (PI3Kγ) deletion]. The inhibition of placental growth factor (PlGF) (HRG) and C/EBPβ (PI3Kγ deletion) also leads to effective reprogramming of TAMs toward M1-like macrophages. Finally, by stimulating CD40, monoclonal antibodies (mAbs) against CD40 similarly reprogram TAMs from M2 phenotype to M1 macrophages.