Immune checkpoint blockade(ICB)therapy is a revolutionary approach to treat cancers,but still have limited clinical applications.Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor micro...Immune checkpoint blockade(ICB)therapy is a revolutionary approach to treat cancers,but still have limited clinical applications.Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment(TME)as one major obstacle.The TME,characterized by acidity,hypoxia and elevated ROS levels,exerts its detrimental effects on infiltrating anti-tumor immune cells.Here,we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles(termed as CAT@CaCO_(3) NPs)as the simple yet versatile multi-modulator for TME remodeling.CaCO_(3) NPs can consume protons in the acidic TME to normalize the TME pH.CAT catalyzed the decomposition of ROS and thus generated O2.The released Ca^(2+)led to Ca^(2+)overload in the tumor cells which then triggered the release of damage-associated molecular patterns(DAMP)signals to initiate anti-tumor immune responses,including tumor antigen presentation by dendritic cells.Meanwhile,CAT@CaCO_(3) NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype,further enhancing tumor antigen presentation.Consequently,T cell-mediated anti-tumor responses were activated,the efficacy of which was further boosted by aPD-1 immune checkpoint blockade.Our study demonstrated that local treatment of CAT@CaCO_(3) NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses,inhibiting the growth of treated tumors and distant diseases.展开更多
基金supported by the start-up package from McGill University(to G.C.)CIHR grants(to G.C.)+2 种基金CCS-Challenge Grants(to G.C.)the Rolande and Marcel Gosselin Graduate Studentship,Dr.Victor KS Lui Studentship,Charlotte and Leo Karassik Foundation Oncology Ph.D.Fellowship from the Rosalind&Morris Goodman Cancer Institute as well as the BME recruitment awardThe authors thank Dr.Peter Siegel at McGill University for providing the 4T1 cell line.
文摘Immune checkpoint blockade(ICB)therapy is a revolutionary approach to treat cancers,but still have limited clinical applications.Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment(TME)as one major obstacle.The TME,characterized by acidity,hypoxia and elevated ROS levels,exerts its detrimental effects on infiltrating anti-tumor immune cells.Here,we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles(termed as CAT@CaCO_(3) NPs)as the simple yet versatile multi-modulator for TME remodeling.CaCO_(3) NPs can consume protons in the acidic TME to normalize the TME pH.CAT catalyzed the decomposition of ROS and thus generated O2.The released Ca^(2+)led to Ca^(2+)overload in the tumor cells which then triggered the release of damage-associated molecular patterns(DAMP)signals to initiate anti-tumor immune responses,including tumor antigen presentation by dendritic cells.Meanwhile,CAT@CaCO_(3) NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype,further enhancing tumor antigen presentation.Consequently,T cell-mediated anti-tumor responses were activated,the efficacy of which was further boosted by aPD-1 immune checkpoint blockade.Our study demonstrated that local treatment of CAT@CaCO_(3) NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses,inhibiting the growth of treated tumors and distant diseases.
