Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This stud...Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.展开更多
Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side eff...Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.展开更多
The aim of neoadjuvant treatment in non-small cell lung cancer(NSCLC)is to eliminate micrometastatic disease to facilitate surgical resection.Neoadjuvant chemotherapy(ChT)in localised NSCLC has numerous advantages ove...The aim of neoadjuvant treatment in non-small cell lung cancer(NSCLC)is to eliminate micrometastatic disease to facilitate surgical resection.Neoadjuvant chemotherapy(ChT)in localised NSCLC has numerous advantages over other therapeutic modalities and is considered standard treatment in resectable disease.Treatment with immune checkpoint inhibitors(ICI)improves long-term survival in advanced disease and has a better toxicity profile than conventional therapies.These immunotherapy agents(anti-PD1/PD-L1),administered with or without ChT,are currently being evaluated in the preoperative setting,with initial results showing better pathological response rates and more long-term benefits.Importantly,these drugs do not appear to increase the rate of severe adverse effects and/or postoperative complications.However,several questions still need to be resolved,including the identification of predictive biomarkers;comparative studies of immunotherapy alone vs combined treatment with ChT and/or radiotherapy;the optimal duration of treatment;the timing of surgery;the need for adjuvant treatment;appropriate radiologic evaluation and mediastinal staging;and the correlation between pathological response and survival outcomes.Here we review the current evidence for immunotherapy from a multidisciplinary perspective and discuss current and future controversies.展开更多
Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical settings.However,immunotherapy resistance is a major challenge for B-cell lymphoma treatment.To overcome this issu...Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical settings.However,immunotherapy resistance is a major challenge for B-cell lymphoma treatment.To overcome this issue,combinatorlal therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas.One of such strategies is to combine immunotherapy with histone deacetylase(HDAC)inhi-bitors.HDAC inhibitors can potentially increase tumor immunogenicity,promote antitumor immune respon-ses,or reverse immunosuppressive tumor environments.Thus,the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment.However,not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target.Hence,we suggest that optimal treatment effh-cacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors.Here,we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.展开更多
基金supported by the National Key Research and Development Program of China[2018YFB0407200]National Natural Science Foundation of China[61975239]Medical and Health Technology Innovation Project of the Chinese Academy of Medical Sciences[2019-I2M-5061].
文摘Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.
基金supported in part by grants from the National Natural Sciences Foundation of China (82130106)Jiangsu Provincial Department of Science and Technology (BK20192005, China)+1 种基金Changzhou Bureau of Science and Technology (CJ20210024, CZ20210010, China)Jiangsu TargetPharma Laboratories Inc., China
文摘Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.
文摘The aim of neoadjuvant treatment in non-small cell lung cancer(NSCLC)is to eliminate micrometastatic disease to facilitate surgical resection.Neoadjuvant chemotherapy(ChT)in localised NSCLC has numerous advantages over other therapeutic modalities and is considered standard treatment in resectable disease.Treatment with immune checkpoint inhibitors(ICI)improves long-term survival in advanced disease and has a better toxicity profile than conventional therapies.These immunotherapy agents(anti-PD1/PD-L1),administered with or without ChT,are currently being evaluated in the preoperative setting,with initial results showing better pathological response rates and more long-term benefits.Importantly,these drugs do not appear to increase the rate of severe adverse effects and/or postoperative complications.However,several questions still need to be resolved,including the identification of predictive biomarkers;comparative studies of immunotherapy alone vs combined treatment with ChT and/or radiotherapy;the optimal duration of treatment;the timing of surgery;the need for adjuvant treatment;appropriate radiologic evaluation and mediastinal staging;and the correlation between pathological response and survival outcomes.Here we review the current evidence for immunotherapy from a multidisciplinary perspective and discuss current and future controversies.
文摘Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical settings.However,immunotherapy resistance is a major challenge for B-cell lymphoma treatment.To overcome this issue,combinatorlal therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas.One of such strategies is to combine immunotherapy with histone deacetylase(HDAC)inhi-bitors.HDAC inhibitors can potentially increase tumor immunogenicity,promote antitumor immune respon-ses,or reverse immunosuppressive tumor environments.Thus,the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment.However,not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target.Hence,we suggest that optimal treatment effh-cacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors.Here,we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.
