Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO

Abstract

Nitric oxide and its production by iNOS is an established mechanism critical to tumor promotion or suppression. Macrophages have important roles in immunity, development, and progression of cancer and have a controversial role in pro- and antitumoral effects. The tumor microenvironment consists of tumor-associated macrophages (TAM), among other cell types that influence the fate of the growing tumor. Depending on the microenvironment and various cues, macrophages polarize into a continuum represented by the M1-like pro-inflammatory phenotype or the anti-inflammatory M2-like phenotype; these two are predominant, while there are subsets and intermediates. Manipulating their plasticity through programming or reprogramming of M2-like to M1-like phenotypes presents the opportunity to maximize tumoricidal defenses. The dual role of iNOS-derived NO also influences TAM activity by repolarization to tumoricidal M1-type phenotype. Regulatory pathways and immunomodulation achieve this through miRNA that may inhibit the immunosuppressive tumor microenvironment. This review summarizes the classical physiology of macrophages and polarization, iNOS activities, and evidence towards TAM reprogramming with current information in glioblastoma and melanoma models, and the immunomodulatory and therapeutic options using iNOS or NO-dependent strategies.

Keywords: M1; M2; arginase; cancer progression; iNOS; miRNA; nitric oxide; tumor-associated macrophage.

Figure 1

Major M1 and M2 differentiation pathways. Briefly, M1-like macrophages (upper panel) can be induced by IFN-γ and LPS-mediated activation of TLR-4 signaling pathway, promoting inflammatory responses by secreting cytokines such as TNF-α, IL-1α, IL-1β, IL-6, IL-12, IL-18, and IL-23. Alternatively, IL-4 and IL-13 induce macrophages to M2-like (lower panel) by activating STAT6 via the IL-4 receptor alpha (IL-4Rα), whereas IL-10 promotes M2 phenotype by activating STAT3 through IL-10R. In the IL-4 and IL-13 pathway, receptor binding of IL-4 activates JAK1 and JAK3 leading to STAT6 activation and translocation.

Figure 2

Repolarization of tumor-associated macrophages. M1-like and M2-like phenotypes shift expression depending on the microenvironment. Could iNOS-derived NO modulate TAMs?

Figure 3

The role of M1-like and M2-like macrophages in apoptosis and angiogenesis.

Figure 4

NO in melanoma tumor-induced immune suppression. Treatments such as CD40 activation and CpG may activate macrophages, produce NO and reduce immune suppression.

Figure 5

Exogenous NO or iNOS-derived NO modulate the macrophage status. M2-type macrophages may be re-polarized into M1 phenotype via regulatory miRNA. ROS-generated oxidative stress may produce a cytocidal profile and reverse tumor progression.