Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer

Abstract

Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

“…Elevated expression of MafB in TAMs was also demonstrated in a mouse model of breast cancer [105]. A recent study found that M2 macrophages induced by IL-4 and IL-13 express high levels of c-Maf that regulates expression of M2-related genes (IL-12, IL-1b, IL-6, ARG1, IL-10, VEGF, TGFb, IRF4, and CCR2) [106]. c-Maf is expressed by TAMs in human non-small cell lung carcinoma (NSCLC), and promotes M2-mediated T cell suppression and tumor progression by controlling M2-related genes in vivo [106].…”

Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement

“…Of interest, in the 3d injured nerve, Mac1, Mac3, and Mac4 strongly express the TFs Maf/c-Maf and Mafb/MafB. MafB promotes reprogramming of macrophages into an M2-like phenotype (Kim, 2017) and c-Maf is a checkpoint that programs Mac and is critical for the acquisition of an immunosuppressive phenotype (Liu et al, 2020).…”

Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis

“…Moreover, both KLF4 and c-Myc, which have been implicated in pluripotent stem cell reprogramming (45), are ERK5 targets (46,47). However, a recent study showed that cMaf was a transcriptional regulator of protumoral macrophage activation (48). In the future, unbiased transcriptomic studies to establish the transcriptional network downstream of ERK5 will be essential to understand how ERK5 maintains proliferative protumor macrophage populations to support tumor progression and malignancy.…”