The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-program...The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be improved.Here,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor therapy.Transfersomes were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:C.Moreover,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune responses.Using a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune activation.This study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.展开更多
Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limit...Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their application.Here,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and adjuvants.Meanwhile,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor efficacy.The fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in vitro.Following subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and tumors.As a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse model.In summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.展开更多
CD4^＋ CD25^＋ regulatory T （Treg） cells express the transcription factor FOXP3 and play an essential role in preventing autoimmunity. Abundant Treg cell accumulation in tumors and tumor draining lymph nodes （TDLNs...CD4^＋ CD25^＋ regulatory T （Treg） cells express the transcription factor FOXP3 and play an essential role in preventing autoimmunity. Abundant Treg cell accumulation in tumors and tumor draining lymph nodes （TDLNs） has been reported to correlate with both poor and favorable prognosis in various cancers, which suggests that Tregs may have multiple effects on antitumor immunity. However, the heterogeneity of tumor- and TDLN-infiltrating Treg cells remains unclear. Here we provide heterogeneity analysis of tumor infiltrating human CD4^＋ Treg cells and their matched adjacent tissues and TDLNs. We defined three different subpopulations of tumor- and TDLN-infiltrating Treg cells by Helios and CCR8 expression in pancreatic ductal adenocarcinoma （PDAC） and confirmed their functional heterogeneity. Helios^＋ CCR8^＋ Treg cells with potent suppressor function and limited IL-2 and IFN-7 secretion were identified in tumors and TDLNs. On the contrary, Helios^- CCR8^- Treg cells have impaired suppressive activity, and elevated expression of pro-inflammatory cytokines. More advanced grades of PDAC have predominantly Helios^＋ CCR8^＋ Treg cells and few Helios^- CCR8^- Treg cells both in tumors and TDLNs that suggests poor prognosis. These data could help further define the role of Treg cells and their functional role in tumors and TDLNs.展开更多
基金work was supported by the National Natural Science Foundation of China(No.31670972)the Taishan Scholar Program,China.
文摘The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be improved.Here,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor therapy.Transfersomes were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:C.Moreover,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune responses.Using a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune activation.This study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.
基金supported by the National Natural Science Foundation of China(No.82341038)Natural Science Foundation of Sichuan Province(No.2022NSFSC1491)+2 种基金China Postdoctoral Science Foundation Grant(No.2019M663534,China)Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System(CARS-SVIDIP)the Fundamental Research Funds for the Central Universities and Sichuan University Postdoctoral Interdisciplinary Innovation Fund.
文摘Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their application.Here,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and adjuvants.Meanwhile,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor efficacy.The fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in vitro.Following subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and tumors.As a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse model.In summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.
基金supported by National Basic Research Program of China(2014CB541803 and 2014CB541903)the National Science Foundation of China(31525008,81330072,31670911,31370863+1 种基金SMCST 14JC1406100)Shanghai Academic Research Leader(16XD1403800)
文摘CD4^＋ CD25^＋ regulatory T （Treg） cells express the transcription factor FOXP3 and play an essential role in preventing autoimmunity. Abundant Treg cell accumulation in tumors and tumor draining lymph nodes （TDLNs） has been reported to correlate with both poor and favorable prognosis in various cancers, which suggests that Tregs may have multiple effects on antitumor immunity. However, the heterogeneity of tumor- and TDLN-infiltrating Treg cells remains unclear. Here we provide heterogeneity analysis of tumor infiltrating human CD4^＋ Treg cells and their matched adjacent tissues and TDLNs. We defined three different subpopulations of tumor- and TDLN-infiltrating Treg cells by Helios and CCR8 expression in pancreatic ductal adenocarcinoma （PDAC） and confirmed their functional heterogeneity. Helios^＋ CCR8^＋ Treg cells with potent suppressor function and limited IL-2 and IFN-7 secretion were identified in tumors and TDLNs. On the contrary, Helios^- CCR8^- Treg cells have impaired suppressive activity, and elevated expression of pro-inflammatory cytokines. More advanced grades of PDAC have predominantly Helios^＋ CCR8^＋ Treg cells and few Helios^- CCR8^- Treg cells both in tumors and TDLNs that suggests poor prognosis. These data could help further define the role of Treg cells and their functional role in tumors and TDLNs.
