In Vivo Inhibition of c-MYC in Myeloid Cells Impairs Tumor-Associated Macrophage Maturation and Pro-Tumoral Activities

Abstract

Although tumor-associated macrophages (TAMs) are involved in tumor growth and metastasis, the mechanisms controlling their pro-tumoral activities remain largely unknown. The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors. In this study, we exploited the predominant expression of LysM in myeloid cells to generate c-Mycfl/fl LysMcre/+ mice, which lack c-Myc in macrophages, to investigate the role of macrophage c-MYC expression in cancer. Under steady-state conditions, immune system parameters in c-Mycfl/fl LysMcre/+ mice appeared normal, including the abundance of different subsets of bone marrow hematopoietic stem cells, precursors and circulating cells, macrophage density, and immune organ structure. In a model of melanoma, however, TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions (e.g., reduced expression of VEGF, MMP9, and HIF1α) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Mycfl/fl LysMcre/+ mice. Macrophage c-Myc deletion also diminished fibrosarcoma growth. These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy.

A unique role for p53 in the regulation of M2 macrophage polarization

“…10,11 It was not clear whether induction of c-MYC in M2-polarized macrophages is a primary event in response to IL4/IL13 stimulation or secondary to STAT6 (signal transducer and activator of transcription 6) activation. To clarify, c-MYC expression in macrophages from wild-type and STAT6-deficient mice was compared.…”

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

“…Interestingly, MYCN has also been recently revealed as the most highly upregulated gene in macrophages upon the treatment of immune suppressive soluble factors that are released from apoptotic cells [48]. Once more, it was shown that inhibition of MYC in macrophages attenuates the protumor function of TAM and suppresses tumor growth [49].…”

Inhibition of MYC in macrophages: tumor vs inflammation-related diseases

“…In this regard, we recently described that inhibiting MYC only in the myeloid compartment in mice reduces melanoma and fibrosarcoma tumor growth. 4,5 TAMs are generally considered "alternatively activated", M2 or M2-like macrophages, a group which refers to all macrophage subtypes which are activated by stimuli different from T helper type 1 (Th1) inflammatory cytokines, showing a specific phenotype and exerting particular functional activities. 6 Among these, the anti-inflammatory properties of M2 macrophages are needed to avoid exacerbated inflammatory responses and inflammation-related pathologies.…”

“…6 Interestingly, mice lacking MYC in myeloid cells show a normal immune system in steady-state conditions compared to control littermates. 4,5 However, in response to an inflammatory stimulus like aortic denudation, these animals are less able to clear and resolve inflammation, which persists for an extended period of time. 7 Although the role of MYC in fully differentiated immune cells has only recently began to be elucidated in detail, assuming that M2 macrophages and other antiinflammatory cells express MYC, 2,8,9 would an antitumor treatment targeting MYC facilitate subsequent inflammationrelated disorders?…”