Antitumor strategies targeting macrophages: the importance of considering the differences in differentiation/polarization processes between human and mouse macrophages

Macrophages are the immune cells that accumulate the most in the majority of established tumors and this accumulation is associated with a poor prognosis. Tumor-associated macrophages (TAMs) produce inflammatory cytokines and growth factors that promote tumor expansion and metastasis. TAMs have recently emerged as targets of choice to restore an efficient antitumor response and to limit tumor growth. Many molecules targeting TAMs are actually evaluated in clinical trials, alone or in combination. While these molecules induce tumor regression and stimulate cytotoxic responses in mouse models of tumor development, results from early clinical trials are less impressive. In this review, we list the biological differences between human and mouse macrophages that help explain the different efficacy of antitumor strategies targeting TAMs between human and animal studies. Differences in the impact of survival and polarization factors and in the cytokines produced and markers expressed as well as the limitations of extrapolations based on in vitro models of TAM-like generation should be considered in order to improve the design and efficacy of antitumor drugs targeting TAMs.