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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 pro-tumor 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 conservative non-coding sequence of csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating TCA cycle and UDP-GlcNAc biosynthesis thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAM) 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 its immunosuppressive activity. Natural compound beta-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.

Authors: Liu M, Tong Z, Ding C, Luo F, Wu S, Wu C, Albeituni S, He L, Hu X, Tieri D, Rouchka EC, Hamada M, Takahashi S, Gibb AA, Kloecker G, Zhang HG, Bousamra M, Hill BG, Zhang X, Yan J,
Journal: J. Clin. Invest.; 2020 Apr 01 ; 130 (4) 2081-2096. doi:10.1172/JCI131335
Year: 2020
PubMed: PMID: 31945018 (Go to PubMed)