The Function And Molecular Mechanism Of Trim24 In Regulating M2 Macrophage Polarization And Its Anti-tumor Immunity

The immune cells in tumor microenvironment,including the macrophage,natural killer cell,dendritic cell and cytotoxic T lymphocytes,form the immune regulation system in tumor.Among these infiltrated immune cells,the M2 polarized tumor-associated macrophage(TAM)is a negative regulator of anti-tumor immunity,and thus promotes the tumor growth and development.However,the molecular mechanism by which regulate TAM polarization is poorly understood.In this study,we took advantage of the genetic mouse model,the subcutaneous inoculation tumor model,as well as the macrophage M2 polarization model,to explore the function and molecular mechanism of Trim24 in regulating macrophage M2 polarization and anti-tumor immunity,through which providing novel targets for the anti-tumor immunotherapy.By using the subcutaneous inoculation tumor model,we found that Trim24 specific deletion in myeloid cells dramatically promoted tumor growth.In addition,loss of Trim24 in myeloid cells caused more tumor-infiltrated TAM,which expressed significantly elevated M2-related genes as compared with wild-type TAM.This phenotype was also confirmed through in vitro macrophage polarization system,which established Trim24 as a negative regulator of IL-4-induced macrophage M2 polarization.Mechanistically,Trim24 mediated IL-4-induced K63-linked ubiquitylation of the acetyltransferase Cbp in macrophage,which promoted the association of Cbp with M2 related transcriptional factor Stat6.This association further promoted Cbp-mediated acetylation of Stat6,which suppressed the binding activity of Stat6 on the promoters of M2-type marker genes,thus inhibiting the transcriptional activity of Stat6 and negatively regulating IL-4-mediated M2-type marker genes expression and M2 macrophage polarization.In conclusion,our present study demonstrated that Trim24 mediated K63-linked ubiquitylation of Cbp and promoted Cbp-mediated Stat6 acetylation,which suppressed IL-4-induced M2 macrophage polarization and TAM polarization,finally leading to the modulation of anti-tumor immunity and thus affecting the tumor growth and development.This work not only offers new theoretical knowledge for the research of macrophage polarization,but also provides potential novel targets for the anti-tumor immunotherapy.