The molecular mechanism of Stat6 acetylation in regulating anti-tumor immunity [Image: Dr. Xiao's group]

Scientists have revealed that the acetylation of signal transducer and activator of transcription 6 (Stat6) could inhibit the polarization of M2-type macrophage, thus regulating anti-tumor immune response, which could be a novel target for tumor immunotherapy.

Tumor-associated macrophages (TAMs) are known to exhibit immunosuppressive M2 phenotype and thus inhibit anti-tumor immune responses. Therefore, targeting TAMs inhibits the progression of tumor growth and metastasis and has thus been applied in clinical treatment of many solid tumors. Stat6 is the master transcription factor to control macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 remains elusive.

A recent work by Dr. Xiao Yichuan's research group at the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences reveals that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage M2 polarization, which in turn suppresses macrophage M2 polarization. Additionally, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation through directly catalyzing CBP ubiquitination at Lys119, which facilitates its recruitment to Stat6. Therefore, the loss of Trim24 dramatically inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, which consequently compromises the anti-tumor immune responses of the macrophages. More interestingly, Stat6 mediates the direct transcriptional suppression of the Trim24 gene in M2 macrophages, which contributes to the immunosuppressive tumor niche.

These findings establish Stat6 acetylation as an essential negative regulatory mechanism that modulates anti-tumor immunity through regulating macrophage M2 polarization and highlight the first identified acetylation site in Stat6.

This research, entitled “Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24”, was published online in Nature Communications on September 25, 2019.

For more information, please contact:

Wang Jin (Ms.)

Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences

Email: sibssc@sibs.ac.cn

Source: Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences