Targeting their recruitment and polarization is the milestone of the TAM-mediated anticancer therapy (Ries et al. 2014). Accordingly, preclinical models strongly support the anti CCL2 therapy in prostate and breast cancer (Qian et al. 2011; Zhang et al. 2010). Anti-CSF-1 antibodies and antisense oligonucleotides have been described to reduce macrophage infiltration and xenograft mammary tumor growth in mice (Aharinejad et al. 2004; Paulus et al. 2006). Quite recently, a new monoclonal antibody inhibiting CSF-1R activation has been developed that strongly reduced F4/80+ TAM infiltration in animal models; in a phase 1 clinical trial, this drug reduced CSF1R + CD163+ TAM with a systemic clinical positive impact in diffuse-type giant cell tumors (Ries et al. 2014). In line with this evidence, another anti-CSF1R antibody has been recently developed which inhibited macrophage polarization toward M2 phenotype, skewing their differentiation toward dendritic cells (Haegel et al. 2013). TAM-targeting may also modulate the response to chemotherapy. In a phase II clinical trial, a partial clinical effect was obtained in patients with advanced pancreatic cancer treated with the fully human CD40 agonist antibody in combination with gemcitabine chemotherapy, likely dependent on a modified macrophage phenotype showing upregulation of MHC class II and CD86 expression (Beatty et al. 2011). Accordingly, in a gallbladder cancer model, the Th1 cytokine IFNγ promoted the antitumor effector functions of CD40 ligand-activated macrophages (Luheshi et al. 2014), and, even though favored monocyte/macrophages recruitment, it inhibited TAM differentiation, reducing VEGF levels and tumor angiogenesis (Sun et al. 2014). In a genetic mouse model of breast cancer, paclitaxel chemotherapy increased CSF1 receptor-expressing TAM: blockade of macrophage recruitment with inhibitors of CSFR1 in combination with chemotherapy-enhanced therapeutic activity, inhibited metastases, and increased T cell infiltration in the tumors (Denardo et al. 2011). Trabectedin is an EMEA-approved natural product derived from the marine organism Ecteinascidia turbinata, displaying potent antitumor activity; it is specifically cytotoxic for human and murine macrophages and TAM (Germano et al. 2010), and targeting TAM has recently been shown to mediate its antitumor action (Germano et al. 2013).

An alternative TAM-targeting strategy could consist on targeting their effector functions. The bisphosphonate zoledronic acid is a classical MMP inhibitor. In cervical cancer, it suppressed TAM-related MMP-9 expression and activity, reducing angiogenesis and carcinogenesis (Giraudo et al. 2004). The bisphosphonate derivative clodronate efficiently depleted TAM in murine teratocarcinoma and human rhabdomyosarcoma mouse models, resulting in inhibition of tumor growth (Zeisberger et al. 2006). Enhanced 15-Lipoxigenase-2 (15-LOX2) activity in renal cell carcinoma (RCC) has been implicated in monocytes recruitment through the CCL2-CCR2 axis. In turn, TAM exerted immunosuppressive actions by inducing FOXP3 and CTLA4 in LOX-independent fashion. Therapeutic approaches aimed at manipulating the 15-LOX2-mediated arachidonic metabolism could be useful to subvert the immunosuppression in patients with RCC (Daurkin et al. 2011).

In addition to blocking their recruitment, differentiation, and effector functions, a line of evidence also suggests that some immunological mediators, such as IFN-γ or IFN-α, could also “reprogram” macrophages from immunosuppressive M2 into immunostimulatory M1 cells, thus adding a new feature to macrophage plasticity and new possibilities to TAM targeted anticancer approaches (Duluc et al. 2009; De Palma et al. 2008).

Advance in understanding the biology of TAM offers new possibilities in developing anticancer strategies aimed at targeting these cells or modulating their function, although further investigation of their features in the context of different tumors may be required to optimize their therapeutic manipulation.