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- Title
Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer.
- Authors
Min Liu; Zan Tong; Chuanlin Ding; Fengling Luo; Shouzhen Wu; Caijun Wu; Albeituni, Sabrin; Liqing He; Xiaoling Hu; Tieri, David; Rouchka, Eric C.; Michito Hamada; Satoru Takahashi; Gibb, Andrew A.; Goetz Kloecker; Huang-ge Zhang; Michael Bousamra II; Bradford G. Hill; Xiang Zhang; Jun Yan
- 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.
- Subjects
TREATMENT of lung tumors; LUNG cancer treatment; TUMOR treatment; LUNG cancer; PROTEINS; RESEARCH; ANIMAL experimentation; RESEARCH methodology; LUNG tumors; MACROPHAGES; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; IMMUNITY; GENES; RESEARCH funding; TUMORS; CELLULAR immunity; CELL lines; T cells; MONOCYTES; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 4, p2081
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI131335