Altering macrophage polarization in the tumor environment: the role of response gene to complement 32

Macrophages in tumors are a major problem. They are dynamic and heterogeneous cells, and their differentiation, tissue distribution and responsiveness to stimuli are governed by distinct mechanisms. In response to certain signals, macrophages can undergo either M1- or M2-type activation, which result in two distinct functional phenotypes. M1/inhibit-type macrophages are (Figure 1) characterized by the production of inducible nitric oxide synthase, its product nitric oxide and tumor necrosis factor-α. By contrast, M2/heal-type macrophages typically express arginase 1, but do not express inducible nitric oxide synthase.¹ M2-type macrophages can switch phenotype to become M1-type macrophages and can kill tumor cells and pathogens through the production of nitric oxide and other inhibitory molecules.² Thus, decreasing the proportion of M2-type and/or increasing the proportion of M1-type macrophages in tumors could be a very promising strategy to inhibit tumor growth and metastases.^3,4,5

Figure 1.

Monocyte recruitment and polarization.

In a study reported in this issue, Zhao et al.⁶ evaluated the expression and role of response gene to complement 32 (RGC-32) in macrophages and tumor-associated macrophages (TAMs). First, they demonstrated that both a cultured macrophage-like cell line and monocyte-derived macrophages up-regulated RGC-32 when exposed to either IL-4 or macrophage colony-stimulating factor. Other products and genes associated with M2/heal-type macrophages were also upregulated, whereas the products associated with M1/inhibit-type macrophages were downregulated. RGC-32 thus appears to be a good marker for M2-type macrophage activity.

Zhao et al.⁶ further showed that ascites tumor fluid enhanced RGC-32 and M2-type cytokines, in accordance with the evidence that either tumors or tumor-associated cells can produce factors that decrease the M1/M2 ratio and inhibit effective antitumor activity.

Because M2-type macrophage activity predominates in tissue macrophages where such cells routinely help repair and replace lost or injured tissue,^7,8 targeting RGC-32 in cancer could have detrimental systemic effects by reducing the activity of M2-type macrophages. However, targeting RGC-32 might also help repolarize macrophages toward M1-type activity, leading to beneficial macrophage antitumor effects.

Regarding the intratumor signals that either maintain or enhance TAM M2-type activity, it is important to note that both M2- and M1-type responses occur in the absence of T cells.⁸ Thus, macrophages do not need to be ‘alternatively activated' (e.g., by IL-4) or ‘activated' (e.g., by IFN-γ), although if T cells are present, they can further augment M2- or M1-type activities.⁸ Therefore, the M2-type macrophage activity in tumors may reflect a combination of the absence of signals (e.g., foreign antigens, Toll ligands, lectins) that activate M1-like activity and the presence of M2-type polarizing signals. Many tumors do not seem to have a significant T-cell component. However, non-T cell-derived colony-stimulating factors, which have been found in many tumors, seem to polarize macrophages toward M2-type activity.⁹ By contrast, T cell-derived IL-4 does not appear to be a common component of either tumors or wounds in which M2-type macrophages predominate.¹⁰ Although the authors showed that IL-4 can increase RGC-32 activity in vitro, T cell-derived IL-4 is unlikely to have a role in polarizing macrophages inside tumors because the IL-4 levels are low within the tumor microenvironment. Thus, it is unclear how anti-IL-4 antibodies could inhibit the apparent M2-polarizing activity of tumor ascites fluid, as described in this report.

TAMs do contribute significantly to tumor angiogenesis by producing a wide array of growth factors such as platelet-derived growth factor and transforming growth factor-β (TGF-β). Interestingly, the authors showed that TGF-β expression could be decreased by inhibiting RGC-32 expression. TGF-β, a macrophage-derived cytokine found in both tumors and wounds, strongly polarizes macrophages toward M2-like activity.^1,7,8

Several strategies have been proposed to target TAMs. Either reducing or eliminating TAMs is an alternative to attempting to polarize them to an alternate phenotype. Further knowledge of the exact molecular mechanisms of TAM-induced angiogenesis and tumor progression, together with a better understanding of the functional diversity of TAMs and their interaction with the tumor microenvironment, may lead to innovative therapeutic strategies for cancer patients.

Thus, the study by Zhao et al.⁶ shows that inhibiting TGF-β by targeting RGC-32 is a promising approach to altering the predominant phenotype of TAMs from M2 to M1. It will be interesting to see whether future studies show that inhibition of RGC-32 activity in vivo can slow cancer growth or otherwise modulate macrophage activity under circumstances in which M1- or M2-type responses are desirable.