Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer
Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, Jun Yan
Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, Jun Yan
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Research Article Immunology

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.

Authors

Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, Jun Yan

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Figure 5

Inhibition of c-Maf in M2 BMDMs partially interrupts TCA cycle and UDP-GlcNAc activity.

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Inhibition of c-Maf in M2 BMDMs partially interrupts TCA cycle and UDP-G...
(A) Schema of TCA cycle and UDP-GlcNAc pathway. (B) M2 BMDMs were treated with c-Maf inhibitor or vehicle control and the mRNA levels of c-Maf, IDH1, and IDH2 are shown. **P < 0.01, ***P < 0.001 by 2-tailed, unpaired t test. (C) M2 BMDMs (n = 3) treated with vehicle or c-Maf inhibitor were labeled with 13C-labeled glucose for 24 hours. Cell extracts were analyzed by mass spectrometry. The data show that the abundance of total αKG and carbon labeling is reduced in M2 BMDMs treated with c-Maf inhibitor. *P < 0.05 by 2-tailed, unpaired t test (top); **P < 0.01 by 2-way ANOVA with Sidak’s multiple-comparisons test (bottom). (D) Inhibition of c-Maf significantly decreases UDP-GlcNAc labeling from 13C-glucose. ****P < 0.0001 by 2-way ANOVA with Sidak’s multiple-comparisons test (left) or by 2-tailed, unpaired t test (right). (E) CD301 expression on M2 BMDMs treated with vehicle or the c-Maf inhibitor Nivalenol (NIV) for 24 hours determined by flow cytometry. MFI, mean fluorescence intensity. Data are shown as mean ± SEM. *P < 0.05 by 1-way ANOVA with Dunnett’s multiple-comparisons test.