Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-t...Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.展开更多
Coronavirus disease 2019(COVID-19)is a global infectious disease that seriously endangers human life and health and affects normal social activities.Since the pandemic outbreak from December 2019 to February 2023,the ...Coronavirus disease 2019(COVID-19)is a global infectious disease that seriously endangers human life and health and affects normal social activities.Since the pandemic outbreak from December 2019 to February 2023,the total number of confirmed cases has exceeded 753 million,and the deaths caused by COVID-19 have reached 6.6 million(https://covid19.who.int;accessed on Feb.16,2023).展开更多
Androgen receptor(AR)mutation is closely associated with prostate cancer(PCa)and is one of the mechanisms of resistance to PCa therapies such as AR antagonists.Although sequencing technologies like next-generation seq...Androgen receptor(AR)mutation is closely associated with prostate cancer(PCa)and is one of the mechanisms of resistance to PCa therapies such as AR antagonists.Although sequencing technologies like next-generation sequencing(NGS)contributes to the high-throughput and precise detection of AR mutations carried by PCa patients,the lack of interpretations of these clinical genetic variants has still been a roadblock for PCa-targeted precision medicine.Here,we established a designer yeast reporter assay to simulate natural androgen receptor(AR)selection using AR antagonists.Yeast HIS3 gene transactivation was associated with the ligand-induced recruitment of steroid receptor coactivator-1(SRC-1)by AR mutants,where yeast growth in histidine-free medium was determined as the outcome.This assay is applicable to determine a wide range of clinical AR mutants including those with loss of function relating to androgen insensitivity syndrome(AIS),and those associated with PCa conferring resistance to AR antagonists such as enzalutamide(ENZ),bicalutamide(BIC),and cyproterone acetate(CPA).One clinical AR mutant previously reported to confer ENZ-resistance,F877L,was found to confer partial resistance to CPA as well using designer yeast.Our simple and efficient assay can enable precise one-pot screening of AR mutants,providing a reference for tailored medicine.展开更多
基金supported by Techpool Bio-Pharma Co.,Ltd.(grant no.AKR-S005).
文摘Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.
基金supported by the Chinese Traditional Medicine Science and Technology Projects of Zhejiang Province (Nos.2021ZB002,2022ZB002,and 2020ZQ002)the National Natural Science Foundation of China (No.31702144)+1 种基金the Zhejiang Province Basic Public Welfare Research Project (No.LGF21H250002)the National Administration of Traditional Chinese Medicine and Zhejiang Province (No.GZY-ZJ-KJ-24001),China.
文摘Coronavirus disease 2019(COVID-19)is a global infectious disease that seriously endangers human life and health and affects normal social activities.Since the pandemic outbreak from December 2019 to February 2023,the total number of confirmed cases has exceeded 753 million,and the deaths caused by COVID-19 have reached 6.6 million(https://covid19.who.int;accessed on Feb.16,2023).
基金This work was supported by National Natural Science Foundation of China under the grants 21621004 and 31861143017 to Y.Y.
文摘Androgen receptor(AR)mutation is closely associated with prostate cancer(PCa)and is one of the mechanisms of resistance to PCa therapies such as AR antagonists.Although sequencing technologies like next-generation sequencing(NGS)contributes to the high-throughput and precise detection of AR mutations carried by PCa patients,the lack of interpretations of these clinical genetic variants has still been a roadblock for PCa-targeted precision medicine.Here,we established a designer yeast reporter assay to simulate natural androgen receptor(AR)selection using AR antagonists.Yeast HIS3 gene transactivation was associated with the ligand-induced recruitment of steroid receptor coactivator-1(SRC-1)by AR mutants,where yeast growth in histidine-free medium was determined as the outcome.This assay is applicable to determine a wide range of clinical AR mutants including those with loss of function relating to androgen insensitivity syndrome(AIS),and those associated with PCa conferring resistance to AR antagonists such as enzalutamide(ENZ),bicalutamide(BIC),and cyproterone acetate(CPA).One clinical AR mutant previously reported to confer ENZ-resistance,F877L,was found to confer partial resistance to CPA as well using designer yeast.Our simple and efficient assay can enable precise one-pot screening of AR mutants,providing a reference for tailored medicine.
