Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrat...Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.展开更多
Tcf12 has been identified as one of the main helix-loop-helix transcription factors that regulates T cell development from double negative to double positive stage transition.While,the function of Tcf12 in hematopoiet...Tcf12 has been identified as one of the main helix-loop-helix transcription factors that regulates T cell development from double negative to double positive stage transition.While,the function of Tcf12 in hematopoietic stem cells remains not investigated.In this study,we observed that Tcf12 is expressed in HSCs and targeted deletion of Tcf12 in hematopoietic cells results in increased frequency and absolute number of HSCs,but compromises the reconstitution capacity of HSCs.Further analysis reveals that Tcf12 is dispensable for the self-renewal of HSCs.The declined reconstituted capacity of Tcf12^(-/-)HSCs stems from the decrease in the ability to differentiate into lymphoid-primed multipotent progenitors,and furthermore B and T lineages.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82372818 to Xiaodong Zhang,82103066 to Guang Yang,82302887 to Hongfeng Yuan,82303210 to Yufei Wang)The China Postdoctoral Science Foundation(No.2022M712389 to Hongfeng Yuan,No.2023M732624 to Yufei Wang,No.2023M742621 to Lina Zhao)+1 种基金Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A to W.Lu,China)“14th Five-Year Plan”Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital(No.YZ-03,China).
文摘Protein arginine methyltransferase 5(PRMT5)acts as an oncogene in liver cancer,yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined.Here,we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8^(+)T-cell-mediated antitumor immunity both in vivo and in vitro.Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule,fibrinogen-like protein 1(FGL1).Mechanistically,PRMT5 catalyzed symmetric dimethylation of transcription factor 12(TCF12)at arginine 554(R554),prompting the binding of TCF12 to FGL1 promoter region,which transcriptionally activated FGL1 in tumor cells.Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression,which promoted CD8^(+)T-cell-mediated antitumor immunity.Notably,combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice.Collectively,our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.
基金This work was supported by grant numbers 2018YFA0800200,2017YFA0104000,Z18110000181800581870118 to JianweiWang from the National Key R&D Program of China+1 种基金the Beijing Municipal Science&Technology Commissionthe National Natural Science Foundation of China.
文摘Tcf12 has been identified as one of the main helix-loop-helix transcription factors that regulates T cell development from double negative to double positive stage transition.While,the function of Tcf12 in hematopoietic stem cells remains not investigated.In this study,we observed that Tcf12 is expressed in HSCs and targeted deletion of Tcf12 in hematopoietic cells results in increased frequency and absolute number of HSCs,but compromises the reconstitution capacity of HSCs.Further analysis reveals that Tcf12 is dispensable for the self-renewal of HSCs.The declined reconstituted capacity of Tcf12^(-/-)HSCs stems from the decrease in the ability to differentiate into lymphoid-primed multipotent progenitors,and furthermore B and T lineages.
