Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated.We developed a mouse model bearing large primary(300 m...Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated.We developed a mouse model bearing large primary(300 mm^(3))and medium distant(100 mm^(3))EG7 lymphomas engineered to express ovalbumin(OVA)as a nominal tumor antigen.We established experimental protocols including IRE alone and IRE combined with Toll-like receptor(TLR)3/9 agonists(poly I:C/CpG)(IRE+pIC/CpG),PD-1 blockade(IRE+PD-1 blockade),or both(IRE+Combo)to investigate therapeutic effects on primary and distant EG7 tumors and conversion-promoting effects on the immunotolerant tumor microenvironment(TME).We demonstrated that IRE alone simulated very weak OVA-specific CD8^(+)T cell responses and did not inhibit primary tumor growth.IRE+pIC/CpG synergistically stimulated more efficient OVA-specific CD8^(+)T cell responses and primary tumor growth inhibition than IRE+PD-1 blockade.IRE+pIC/CpG played a major role in the modulation of immune cell profiles but a minor role in the downregulation of PD-L1 expression in the TME and vice versa for IRE+PD-1 blockade.IRE+Combo cooperatively induced potent OVA-specific CD8^(+)T cell immunity and rescued exhausted intratumoral CD8^(+)T cells,leading to eradication of not only primary tumors but also untreated concomitant distant tumors and lung metastases.IRE+Combo efficiently modulated immune cell profiles,as evidenced by reductions in immunotolerant type-2(M2)macrophages,myeloid-derived suppressor-cells,plasmacytoid dendritic cells,and regulatory T cells and by increases in immunogenic M1 macrophages,CD169^(+)macrophages,type-1 conventional dendritic cells,and CD8^(+)T cells,leading to conversion of immunotolerance in not only primary TMEs but also untreated distant TMEs.IRE+Combo also showed effective therapeutic effects in two breast cancer models.Therefore,our results suggest that IRE+Combo is a promising strategy to improve IRE ablation therapy in cancer.展开更多
Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secrete...Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secreted by immune cells.The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1.ADA2 has distinct characteristics,such as low adenosine affinity,heparin-binding ability,and putative lysosomal entry.Here,we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9(TLR9)agonists,specifically CpG oligodeoxynucleotides(CpG ODNs).We show that interferon-alpha(IFN-α)is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells(pDCs).Additionally,the pretreatment of pDCs with RNA further stimulates IFN-αsecretion by pDCs after activation with CpG ODNs.Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs.In conclusion,decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-αsecretion from pDCs,improving immune responses against intracellular infections and cancer.展开更多
Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to...Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor＇s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA （mtDNA） activates several innate immune path- ways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibac- terial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.展开更多
文摘Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated.We developed a mouse model bearing large primary(300 mm^(3))and medium distant(100 mm^(3))EG7 lymphomas engineered to express ovalbumin(OVA)as a nominal tumor antigen.We established experimental protocols including IRE alone and IRE combined with Toll-like receptor(TLR)3/9 agonists(poly I:C/CpG)(IRE+pIC/CpG),PD-1 blockade(IRE+PD-1 blockade),or both(IRE+Combo)to investigate therapeutic effects on primary and distant EG7 tumors and conversion-promoting effects on the immunotolerant tumor microenvironment(TME).We demonstrated that IRE alone simulated very weak OVA-specific CD8^(+)T cell responses and did not inhibit primary tumor growth.IRE+pIC/CpG synergistically stimulated more efficient OVA-specific CD8^(+)T cell responses and primary tumor growth inhibition than IRE+PD-1 blockade.IRE+pIC/CpG played a major role in the modulation of immune cell profiles but a minor role in the downregulation of PD-L1 expression in the TME and vice versa for IRE+PD-1 blockade.IRE+Combo cooperatively induced potent OVA-specific CD8^(+)T cell immunity and rescued exhausted intratumoral CD8^(+)T cells,leading to eradication of not only primary tumors but also untreated concomitant distant tumors and lung metastases.IRE+Combo efficiently modulated immune cell profiles,as evidenced by reductions in immunotolerant type-2(M2)macrophages,myeloid-derived suppressor-cells,plasmacytoid dendritic cells,and regulatory T cells and by increases in immunogenic M1 macrophages,CD169^(+)macrophages,type-1 conventional dendritic cells,and CD8^(+)T cells,leading to conversion of immunotolerance in not only primary TMEs but also untreated distant TMEs.IRE+Combo also showed effective therapeutic effects in two breast cancer models.Therefore,our results suggest that IRE+Combo is a promising strategy to improve IRE ablation therapy in cancer.
文摘Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secreted by immune cells.The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1.ADA2 has distinct characteristics,such as low adenosine affinity,heparin-binding ability,and putative lysosomal entry.Here,we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9(TLR9)agonists,specifically CpG oligodeoxynucleotides(CpG ODNs).We show that interferon-alpha(IFN-α)is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells(pDCs).Additionally,the pretreatment of pDCs with RNA further stimulates IFN-αsecretion by pDCs after activation with CpG ODNs.Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs.In conclusion,decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-αsecretion from pDCs,improving immune responses against intracellular infections and cancer.
文摘Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and con. sidered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor＇s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA （mtDNA） activates several innate immune path- ways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibac- terial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.
