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
To find a feasible method for the stimulation of tumor-draining lymph node （TDLN） cells in preparation for use in the clinic, the CTL activity of TDLN cells induced by different stimuli （IL-2 alone, IL-2 ＋ autolog...To find a feasible method for the stimulation of tumor-draining lymph node （TDLN） cells in preparation for use in the clinic, the CTL activity of TDLN cells induced by different stimuli （IL-2 alone, IL-2 ＋ autologous tumor antigen （atAg）, IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg） was measured by maximal LDH enzyme release. The mechanisms were explored by the observation of morphology and the detection of CD83^＋ TDLN cells. The expansion of TDLN cells by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was significantly higher than that by IL-2 alone or IL-2 ＋ atAg （p 〈 0.01）. Antitumor CTL activity of TDLN cells induced by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was significantly higher than those of other groups. The number of CD83^＋ cells within the TDLN population treated with IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was significantly elevated. The method of stimulating TDLN cells by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was better than the stimulation with IL-2 or IL-2 ＋ atAg. TDLN cells induced by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg produced more dendritic cells （DCs）. In our study, we established a system that T cells and DCs were stimulated together ex vivo, which was easy to conduct and produce promising results. It provided a new method for improving TDLN cell antitumor activity which might be used in the clinical cancer therapy. Cellular ＆ Molecular Immunology. 2008;5（4）：307-313.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.
文摘To find a feasible method for the stimulation of tumor-draining lymph node （TDLN） cells in preparation for use in the clinic, the CTL activity of TDLN cells induced by different stimuli （IL-2 alone, IL-2 ＋ autologous tumor antigen （atAg）, IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg） was measured by maximal LDH enzyme release. The mechanisms were explored by the observation of morphology and the detection of CD83^＋ TDLN cells. The expansion of TDLN cells by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was significantly higher than that by IL-2 alone or IL-2 ＋ atAg （p 〈 0.01）. Antitumor CTL activity of TDLN cells induced by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was significantly higher than those of other groups. The number of CD83^＋ cells within the TDLN population treated with IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was significantly elevated. The method of stimulating TDLN cells by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg was better than the stimulation with IL-2 or IL-2 ＋ atAg. TDLN cells induced by IL-2 ＋ GM-CSF ＋ IL-4 ＋ atAg produced more dendritic cells （DCs）. In our study, we established a system that T cells and DCs were stimulated together ex vivo, which was easy to conduct and produce promising results. It provided a new method for improving TDLN cell antitumor activity which might be used in the clinical cancer therapy. Cellular ＆ Molecular Immunology. 2008;5（4）：307-313.
