Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers,which benefits from tumor downstaging.However,the utility of chemotherapeutics alone as a neoadjuvant agent is incapable...Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers,which benefits from tumor downstaging.However,the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence.Herein,a tactical nanomissile(TALE),equipped with a guidance system(PD-L1 monoclonal antibody),ammunition(mitoxantrone,Mit),and projectile bodies(tertiary amines modified azobenzene derivatives),is designed as a neoadjuvant chemo-immunotherapy setting,which aims at targeting tumor cells,and fast-releasing Mit owing to the intracellular azoreductase,thereby inducing immunogenic tumor cells death,and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system.The formed in situ tumor vaccine can recruit and activate antigen-presenting cells,and ultimately increase the infiltration of CD8^(+)T cells while reversing the immunosuppression microenvironment.Moreover,this approach provokes a robust systemic immune response and immunological memory,as evidenced by preventing 83.3%of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model.Collectively,our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.展开更多
Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor ...Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.展开更多
The complexity and fragmentation of people’s activity space are challenging to planners.However,the relevant studies are mostly concerned on the relationship between the social attributes and the activity space of re...The complexity and fragmentation of people’s activity space are challenging to planners.However,the relevant studies are mostly concerned on the relationship between the social attributes and the activity space of residents in a single or several communities,or the spatiotemporal laws of activity space on a macro scale.The research on the spatial characteristics of residents’activity space still needs to be strengthened.The present study analyses the spatial patterns of residents’activity space based on mobile phone signaling data to fill the gap of previous studies that assessed residents’activity space across small geographic areas.First,according to the spatial scope and direction of an activity space and residents’activity coverage rate,spatial patterns can be divided into three types:compact,extended,and directional extension patterns.The CatBoost method is then used to statistically analyze the influencing variables of spatial patterns,and the order of importance of the following influencing factors is determined:the built environment is more influential than social and economic situations.This study aims to strengthen the understanding of residents’activity space at the spatial level and provide a basis for the optimization of communities with different spatial patterns.展开更多
基金supported by National Key Social Science Research Project(11&ZD042)Forestry Public Welfare Scientific Research Project of the State Forestry Administration in China(200904003)DAAD-K.C.Wong Postdoctoral Fellowship Programme,Germany
基金financially supported by the National Natural Science Foundation of China(82172094)Funds of Sichuan Province for Distinguished Young Scholar(2021JDJQ0037,China)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYYC08002,China)。
文摘Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers,which benefits from tumor downstaging.However,the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence.Herein,a tactical nanomissile(TALE),equipped with a guidance system(PD-L1 monoclonal antibody),ammunition(mitoxantrone,Mit),and projectile bodies(tertiary amines modified azobenzene derivatives),is designed as a neoadjuvant chemo-immunotherapy setting,which aims at targeting tumor cells,and fast-releasing Mit owing to the intracellular azoreductase,thereby inducing immunogenic tumor cells death,and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system.The formed in situ tumor vaccine can recruit and activate antigen-presenting cells,and ultimately increase the infiltration of CD8^(+)T cells while reversing the immunosuppression microenvironment.Moreover,this approach provokes a robust systemic immune response and immunological memory,as evidenced by preventing 83.3%of mice from postsurgical metastasis or recurrence in the B16-F10 tumor mouse model.Collectively,our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.
文摘Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.
基金This work was supported by the National Natural Science Foundation of China[grant numbers 51778125].
文摘The complexity and fragmentation of people’s activity space are challenging to planners.However,the relevant studies are mostly concerned on the relationship between the social attributes and the activity space of residents in a single or several communities,or the spatiotemporal laws of activity space on a macro scale.The research on the spatial characteristics of residents’activity space still needs to be strengthened.The present study analyses the spatial patterns of residents’activity space based on mobile phone signaling data to fill the gap of previous studies that assessed residents’activity space across small geographic areas.First,according to the spatial scope and direction of an activity space and residents’activity coverage rate,spatial patterns can be divided into three types:compact,extended,and directional extension patterns.The CatBoost method is then used to statistically analyze the influencing variables of spatial patterns,and the order of importance of the following influencing factors is determined:the built environment is more influential than social and economic situations.This study aims to strengthen the understanding of residents’activity space at the spatial level and provide a basis for the optimization of communities with different spatial patterns.
