c-Maf: a bad influence in the education of macrophages

Abstract

Tumor-associated macrophages (TAMs) represent the most abundant hematopoietic cell type in the solid tumor microenvironment. TAMs drive T cell inhibition, promote angiogenesis, and produce tumor growth factors. Although they can paradoxically exert antitumor activity and prime protective immunity, the pathways driving this phenotype remain unclear. In this issue of the JCI, Liu and colleagues identified the c-Maf transcription factor as a master regulator of protumoral TAM polarization. The authors found that c-Maf promoted TAMs' immunosuppressive activity, governed their metabolic programming, and drove expression of the macrophage differentiation protein, CSF1R. Further, inhibiting c-Maf in myeloid progenitors, and consequent myeloid-lineage cells, including TAMs, delayed tumor growth. Importantly, β-glucan treatment reduced c-MAF expression in macrophages and monocytes from patients with non-small cell lung cancer (NSCLC) where c-MAF is overexpressed. These results reveal mechanisms whereby myeloid cells drive human cancer progression by thwarting protective immunity and could lead to immunotherapy for most solid malignancies.

Figure 1. c-Maf promotes M2 polarization in TAMs.

In NSCLC, macrophages upregulate the expression of c-Maf, which transcriptionally regulates the expression of Csfr1 and promotes functional and metabolic polarization to M2-like phenotypes and drives T cell suppression. Liu et al. describe that inhibition or elimination of c-Maf in macrophages reprograms their metabolism and function to M1-like cells that promote antitumor responses.