Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the imm...Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines.Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously.When the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA translation.The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes.Immunization with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model.Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.展开更多
The lung is one of the most common sites for cancer metastasis.Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells.Therefore,down-regula...The lung is one of the most common sites for cancer metastasis.Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells.Therefore,down-regulating the production of collagens may contribute to the inhibition of lung metastasis.It has been suggested that mi R-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens.Indeed,our clinical lung tumor data shows that mi R-29 a-3 p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients’outcomes.However,suitable carriers need to be selected to deliver this therapeutic mi RNA to the lungs.In this study,we found that the chemotherapy drug cisplatin facilitated mi R-29 a-3 p accumulation in the exosomes of lung tumor cells,and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation.To scale up the preparation and simplify the delivery system,we designed a lung-targeting liposomal nanovesicle(by adjusting the molar ratio of DOTAP/cholesterol-mi RNAs to 4:1)to carry mi R-29 a-3 p and mimic the exosomes.This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo,thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.展开更多
Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors gr...Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors grew progressively.Mice rejected IL-4-producing tumors got long-lasting anti-tumor immunity.The comparative study showed that IL-4 induced the most effective immune response among several cytokines in both prophylactic and therapeutic models.All of these indicate IL-4 has strong potential as a tumor therapy agent.However,contrary evidence indeed exists,and is becoming more and more abundant which shows IL-4 is a tumor-promoting molecule.IL-4 amounts are usually elevated in human cancer patients.IL-4 knockout mice are more resistant to tumor challenge than IL-4 competent mice.Furthermore,tumor cells of various histological origins often express increased levels of IL-4 receptor in comparison to their normal counterparts.By carefully examining presently available data,we found the effects of IL-4 in tumor immunity are closely related to its sources,expressing time and dose,as well as the molecular and cellular environments.In this mini-review,we concentrate on illustrating the paradoxical roles and underlying mechanisms of IL-4 in tumor immunity and try to understand how one molecule has opposite effects.展开更多
Rheumatoid arthritis(RA)is exacerbated by TNF-alpha signaling.However,it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors.Here,we showed that soluble glycosylated interle...Rheumatoid arthritis(RA)is exacerbated by TNF-alpha signaling.However,it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors.Here,we showed that soluble glycosylated interleukin-17 receptor D(sIL-17RD),which was produced by proteolytic cleavage,enhanced TNF-α-induced RA.We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-αexpression in macrophages.Intriguingly,sIL-17RD was elevated in the sera of arthritic mice and rats.Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering,leading to the accelerated development of collagen-induced arthritis.Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response.Targeting sIL-17RD may provide a new strategy for the therapy of RA.展开更多
Myeloid-derived suppressor cells(MDSCs)are well known for their capacity to suppress antitumor T-cell responses,but their effects on B-cell function and antibody production remain unclear.Here,we found that MDSCs that...Myeloid-derived suppressor cells(MDSCs)are well known for their capacity to suppress antitumor T-cell responses,but their effects on B-cell function and antibody production remain unclear.Here,we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B cells.In the presence of MDSCs,the antibody reaction to a surrogate antigen was significantly enhanced in mice,especially the immunoglobulin(Ig)A subtype.Co-culture with MDSCs promoted both proliferation and differentiation of B cells into IgA-producing plasma cells in vitro.Interestingly,the cross talk between MDSCs and B cells required cell-cell contact.MDSCs from tumor necrosis factor receptor(TNFR)2^(−/−)mice,but not from TNFR1^(−/−)mice,failed to promote B-cell responses.Further investigation suggested that interleukin-10 and transforming growth factor-β1 were crucial for the MDSC-mediated promotion of IgA responses.These results demonstrate a novel mechanism of MDSC-mediated immune regulation during tumor growth.展开更多
Mounting evidence has demonstrated that CD4^(+)T cells play an important role in anti-tumor immune responses.Thus,adoptive transfer of these cells may have great potential for anti-cancer therapy.However,due to the di...Mounting evidence has demonstrated that CD4^(+)T cells play an important role in anti-tumor immune responses.Thus,adoptive transfer of these cells may have great potential for anti-cancer therapy.However,due to the difficulty to generate sufficient tumor-specific CD4^(+)T cells,the use of CD4^(+)T cells in tumor therapy is limited.It has been found that IL-15 transfection enhances the proliferation and anti-tumor activity of tumor-specific CD8+Tcells,but the effect of IL-15 transfection on CD4^(+)T cells remains unknown.Here,the effects of retrovirusmediated IL-15 expression in Ova-specific CD4^(+)T cells from Do11.10 mice were evaluated and it was discovered that IL-15 transfected CD4^(+)T cells expressed both soluble and membrane-bound IL-15.Retrovirusmediated IL-15 expression led to a selective expansion of antigen-specific CD4^(+)T cells by inhibiting their apoptosis.In vivo IL-15 transfected CD4^(+)T cells were more effective in suppressing tumor growth than control retroviral vector transfected ones.To ensure the safety of the method,the employment of thymidine kinase gene made it possible to eliminate these transgenic CD4^(+)T cells following ganciclovir treatment.Together,we show that IL-15 transfection induced a selective expansion of antigen-specific CD4^(+)T cells ex vivo and enhanced their tumor-suppression effects in vivo.This has an important significance for improving the efficacy of adoptive T cell therapy.展开更多
Impaired tumor necrosis factor receptor-1(TNFR-1)signaling has been found in some malignant tumors with poor prognosis.However,the exact role of TNFR-1 signaling in fi brosarcoma remains unclear.Here,we explored the q...Impaired tumor necrosis factor receptor-1(TNFR-1)signaling has been found in some malignant tumors with poor prognosis.However,the exact role of TNFR-1 signaling in fi brosarcoma remains unclear.Here,we explored the question by comparing the growth of TNFR-1 deficient(Tnfr1-)and TNFR-1 competent(Tnfr1+)fibrosarcoma FB61 cells(FB61-m and FB61-R1)in mice.TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro.Moreover,reduced FB61-R1 tumor growth was also obtained in T NFR-1 knockout mice.The mechanism relies mainly on the TNFR-1-mediated down-regulation of vascular endothelial growth factor(VEGF)production by tumor cells.Importantly,treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth,followed by a quick r emission.However,when FB61-R1 tumors were treated with melphalan,tumor growth was similarly delayed at fi rst and then completely rejected.Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fi brosarcoma,and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.展开更多
Persistently high serum levels of soluble tumor-necrosis factor(TNF)receptor 2(sTNFR2)have been observed in septic shock and many inflammatory diseases.However,its origin and regulation during these pathological proce...Persistently high serum levels of soluble tumor-necrosis factor(TNF)receptor 2(sTNFR2)have been observed in septic shock and many inflammatory diseases.However,its origin and regulation during these pathological processes are still largely unknown.In this study,murine bone marrow(BM)chimeras selectively expressing TNFR2 on either BM-derived or non-BM-derived cells were generated and challenged with lipopolysaccharide(LPS).The results show that TNFR2 expression on non-BM-derived cells is crucial for both the sensitivity of mice to LPS and the downregulation of sTNFR2 in serum.Most importantly,sTNFR2 was released from both BM-and non-BM-derived cells.Non-BM TNFR1 expression influenced the sensitivity of mice to LPS challenge but not the level of serum sTNFR2.These results provide the first in vivo evidence for the origin and regulation of sTNFR2 in serum and could aid in the development of novel anti-TNF strategies against septic shock.展开更多
Dear Editor,Strokes cause 5.8 million deaths each year.Among these victims,~30% are from China1.Acute ischemic stroke(AIS)is the most prevalent subtype of strokes.Although drugs can alleviate the symptoms,the recoveri...Dear Editor,Strokes cause 5.8 million deaths each year.Among these victims,~30% are from China1.Acute ischemic stroke(AIS)is the most prevalent subtype of strokes.Although drugs can alleviate the symptoms,the recoveries of functional vessels within ischemic areas are the critical factor determining the prognosis of patients suffering from AIS2.Nevertheless,the mechanisms involved in cerebral revascularization remain largely unknown.展开更多
基金supported by the National Key Research and Development Program of China(No.2021YFA1201102)Henan Medical Science and Technology Joint Building Program(No.SBGJ202102132)+2 种基金Henan Province Youth Talent Promoting Project(No.2022HYTP047)the National Natural Science Foundation of China(Nos.82003255,82101385 and 82073231)Key Research and Development Project of Henan Province(No.232102311224)and First-Class Clinical Medicine Discipline Construction Talents Cultivation Project of Zhengzhou University.
文摘Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines.Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines.Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously.When the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA translation.The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes.Immunization with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model.Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.
基金supported by the National Natural Science Foundation of China(Grant Nos.81630068,31670881,and 81901466)China Postdoctoral Science Foundation(Grant No.2020TQ0282)。
文摘The lung is one of the most common sites for cancer metastasis.Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells.Therefore,down-regulating the production of collagens may contribute to the inhibition of lung metastasis.It has been suggested that mi R-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens.Indeed,our clinical lung tumor data shows that mi R-29 a-3 p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients’outcomes.However,suitable carriers need to be selected to deliver this therapeutic mi RNA to the lungs.In this study,we found that the chemotherapy drug cisplatin facilitated mi R-29 a-3 p accumulation in the exosomes of lung tumor cells,and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation.To scale up the preparation and simplify the delivery system,we designed a lung-targeting liposomal nanovesicle(by adjusting the molar ratio of DOTAP/cholesterol-mi RNAs to 4:1)to carry mi R-29 a-3 p and mimic the exosomes.This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo,thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.
基金This work was supported by Chinese Academy of Sciences(KSCX2-YW-R-42)National Natural Science Foundation of China(30771972 and 30700287)+1 种基金Ministry of Science and Technology of China(2006CB504304,2006CB910901,and 2009CB918900)Ministry of Education,Culture,Sports,Science and Technology(MEXT)of Japan.
文摘Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors grew progressively.Mice rejected IL-4-producing tumors got long-lasting anti-tumor immunity.The comparative study showed that IL-4 induced the most effective immune response among several cytokines in both prophylactic and therapeutic models.All of these indicate IL-4 has strong potential as a tumor therapy agent.However,contrary evidence indeed exists,and is becoming more and more abundant which shows IL-4 is a tumor-promoting molecule.IL-4 amounts are usually elevated in human cancer patients.IL-4 knockout mice are more resistant to tumor challenge than IL-4 competent mice.Furthermore,tumor cells of various histological origins often express increased levels of IL-4 receptor in comparison to their normal counterparts.By carefully examining presently available data,we found the effects of IL-4 in tumor immunity are closely related to its sources,expressing time and dose,as well as the molecular and cellular environments.In this mini-review,we concentrate on illustrating the paradoxical roles and underlying mechanisms of IL-4 in tumor immunity and try to understand how one molecule has opposite effects.
基金This work was supported by grants from the Chinese National Major Scientific Research Program(2016YFA0500301)from the National Natural Science Foundation of China(NSFC)(81872244,81830092,and 81572729).
文摘Rheumatoid arthritis(RA)is exacerbated by TNF-alpha signaling.However,it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors.Here,we showed that soluble glycosylated interleukin-17 receptor D(sIL-17RD),which was produced by proteolytic cleavage,enhanced TNF-α-induced RA.We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-αexpression in macrophages.Intriguingly,sIL-17RD was elevated in the sera of arthritic mice and rats.Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering,leading to the accelerated development of collagen-induced arthritis.Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response.Targeting sIL-17RD may provide a new strategy for the therapy of RA.
基金supported by the Ministry of Science and Technology of China(2012CB917103,2012CB934003)the National Natural Science Foundation of China(91229203)the German Research Foundation(DFG 749-6/1 and SFB 633)。
文摘Myeloid-derived suppressor cells(MDSCs)are well known for their capacity to suppress antitumor T-cell responses,but their effects on B-cell function and antibody production remain unclear.Here,we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B cells.In the presence of MDSCs,the antibody reaction to a surrogate antigen was significantly enhanced in mice,especially the immunoglobulin(Ig)A subtype.Co-culture with MDSCs promoted both proliferation and differentiation of B cells into IgA-producing plasma cells in vitro.Interestingly,the cross talk between MDSCs and B cells required cell-cell contact.MDSCs from tumor necrosis factor receptor(TNFR)2^(−/−)mice,but not from TNFR1^(−/−)mice,failed to promote B-cell responses.Further investigation suggested that interleukin-10 and transforming growth factor-β1 were crucial for the MDSC-mediated promotion of IgA responses.These results demonstrate a novel mechanism of MDSC-mediated immune regulation during tumor growth.
基金supported by the National Basic Research Program(973 Program)(No.2006CB504304)the National Programs for High Technology Research and Development Program(863 Program)(No.2006AA02Z4B9).
文摘Mounting evidence has demonstrated that CD4^(+)T cells play an important role in anti-tumor immune responses.Thus,adoptive transfer of these cells may have great potential for anti-cancer therapy.However,due to the difficulty to generate sufficient tumor-specific CD4^(+)T cells,the use of CD4^(+)T cells in tumor therapy is limited.It has been found that IL-15 transfection enhances the proliferation and anti-tumor activity of tumor-specific CD8+Tcells,but the effect of IL-15 transfection on CD4^(+)T cells remains unknown.Here,the effects of retrovirusmediated IL-15 expression in Ova-specific CD4^(+)T cells from Do11.10 mice were evaluated and it was discovered that IL-15 transfected CD4^(+)T cells expressed both soluble and membrane-bound IL-15.Retrovirusmediated IL-15 expression led to a selective expansion of antigen-specific CD4^(+)T cells by inhibiting their apoptosis.In vivo IL-15 transfected CD4^(+)T cells were more effective in suppressing tumor growth than control retroviral vector transfected ones.To ensure the safety of the method,the employment of thymidine kinase gene made it possible to eliminate these transgenic CD4^(+)T cells following ganciclovir treatment.Together,we show that IL-15 transfection induced a selective expansion of antigen-specific CD4^(+)T cells ex vivo and enhanced their tumor-suppression effects in vivo.This has an important significance for improving the efficacy of adoptive T cell therapy.
基金supported by the Ministry of Science and Technology of China(Grant No.2012CB917103)National Natural Science Foundation of China(Grant Nos.81030049 and 91229203).
文摘Impaired tumor necrosis factor receptor-1(TNFR-1)signaling has been found in some malignant tumors with poor prognosis.However,the exact role of TNFR-1 signaling in fi brosarcoma remains unclear.Here,we explored the question by comparing the growth of TNFR-1 deficient(Tnfr1-)and TNFR-1 competent(Tnfr1+)fibrosarcoma FB61 cells(FB61-m and FB61-R1)in mice.TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro.Moreover,reduced FB61-R1 tumor growth was also obtained in T NFR-1 knockout mice.The mechanism relies mainly on the TNFR-1-mediated down-regulation of vascular endothelial growth factor(VEGF)production by tumor cells.Importantly,treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth,followed by a quick r emission.However,when FB61-R1 tumors were treated with melphalan,tumor growth was similarly delayed at fi rst and then completely rejected.Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fi brosarcoma,and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.
基金grants from the National Natural Science Foundation of China(81030049 and 30700287).
文摘Persistently high serum levels of soluble tumor-necrosis factor(TNF)receptor 2(sTNFR2)have been observed in septic shock and many inflammatory diseases.However,its origin and regulation during these pathological processes are still largely unknown.In this study,murine bone marrow(BM)chimeras selectively expressing TNFR2 on either BM-derived or non-BM-derived cells were generated and challenged with lipopolysaccharide(LPS).The results show that TNFR2 expression on non-BM-derived cells is crucial for both the sensitivity of mice to LPS and the downregulation of sTNFR2 in serum.Most importantly,sTNFR2 was released from both BM-and non-BM-derived cells.Non-BM TNFR1 expression influenced the sensitivity of mice to LPS challenge but not the level of serum sTNFR2.These results provide the first in vivo evidence for the origin and regulation of sTNFR2 in serum and could aid in the development of novel anti-TNF strategies against septic shock.
基金This work was supported by the National Natural Science Foundation of China(81630068,31670881,81502628,and U1304804)the Health Commission of Henan Province(YXKC2020056 and 201702013).
文摘Dear Editor,Strokes cause 5.8 million deaths each year.Among these victims,~30% are from China1.Acute ischemic stroke(AIS)is the most prevalent subtype of strokes.Although drugs can alleviate the symptoms,the recoveries of functional vessels within ischemic areas are the critical factor determining the prognosis of patients suffering from AIS2.Nevertheless,the mechanisms involved in cerebral revascularization remain largely unknown.