Triple-negative breast cancer(TNBC)is highly malignant and refractory to immunotherapy through impeding the immune cell infiltration and inflammation in the tumor microenvironment(TME).1 DNA-dependent protein kinase c...Triple-negative breast cancer(TNBC)is highly malignant and refractory to immunotherapy through impeding the immune cell infiltration and inflammation in the tumor microenvironment(TME).1 DNA-dependent protein kinase catalytic subunit(DNA-PKcs)is a member of the phosphatidylinositol 3-kinase-related kinase family,which is required for the non-homologous end joining repair.2 The effect of DNA-PKcs on the generation of cytosolic DNA and inflammation response in tumor immuno-environment is not defined.We found a specific DNA-PKcs inhibitor,NU7441,induced cytosolic DNA,stimulator of interferon genes(STING),and retinoic acid-inducible gene I(RIG-I)signals in vitro.In Balb/c immune-competent mice bearing 4T1 TNBC cells,NU7441 impaired the tumor growth and metastasis,and increased the CD45+leukocytes,CD4+T cells,CD8+T cells,and CD1a+antigen-presenting cells,as well as MHC-I and interferon alpha receptor(IFNAR)in TME.However,in Balb/c athymic nude mice without IFNAR and CD8+T cells in TME,NU7741 did not influence tumor growth.These results show that inhibition of DNA-PKcs triggers cytosolic DNA sensing and induces an inflamed TME to promote anti-tumoral immunity,which provides a strategy to alter the inflammation and lymphocyte infiltration in TME to increase the efficacy of immunotherapy in TNBC and other cancers with an immune-suppressive TME.展开更多
基金supported by Dalian Medical University Yingcai Project(China)to W.M.and Liaoning Provincial Program for Top Discipline of Basic Medical Sciences(China).
文摘Triple-negative breast cancer(TNBC)is highly malignant and refractory to immunotherapy through impeding the immune cell infiltration and inflammation in the tumor microenvironment(TME).1 DNA-dependent protein kinase catalytic subunit(DNA-PKcs)is a member of the phosphatidylinositol 3-kinase-related kinase family,which is required for the non-homologous end joining repair.2 The effect of DNA-PKcs on the generation of cytosolic DNA and inflammation response in tumor immuno-environment is not defined.We found a specific DNA-PKcs inhibitor,NU7441,induced cytosolic DNA,stimulator of interferon genes(STING),and retinoic acid-inducible gene I(RIG-I)signals in vitro.In Balb/c immune-competent mice bearing 4T1 TNBC cells,NU7441 impaired the tumor growth and metastasis,and increased the CD45+leukocytes,CD4+T cells,CD8+T cells,and CD1a+antigen-presenting cells,as well as MHC-I and interferon alpha receptor(IFNAR)in TME.However,in Balb/c athymic nude mice without IFNAR and CD8+T cells in TME,NU7741 did not influence tumor growth.These results show that inhibition of DNA-PKcs triggers cytosolic DNA sensing and induces an inflamed TME to promote anti-tumoral immunity,which provides a strategy to alter the inflammation and lymphocyte infiltration in TME to increase the efficacy of immunotherapy in TNBC and other cancers with an immune-suppressive TME.
