Tumor cell-intrinsic programmed death-ligand 1(PD-L1)signals mediate tumor initiation,progression and metastasis,but their effects in ameloblastoma(AM)have not been reported.In this comprehensive study,we observed mar...Tumor cell-intrinsic programmed death-ligand 1(PD-L1)signals mediate tumor initiation,progression and metastasis,but their effects in ameloblastoma(AM)have not been reported.In this comprehensive study,we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates.Notably,we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT^(+)-AM cells,whereas genetic ablation of PD-L1 exerted opposing inhibitory effects.By performing highresolution single-cell profiling and thorough immunohistochemical analyses in AM patients,we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors.Our findings revealed that hTERT^(+)-AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial-mesenchymal transition.This phenotypic shift is induced by the activation of the PI3KAKT-mTOR signaling axis;thus,this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence.Importantly,targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patientderived tumor organoids,highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.展开更多
Gastric cancer(GC)is the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide,with China bearing nearly half of the global burden[1,2].Most patients are diagnosed at stage Ⅲ–Ⅳ...Gastric cancer(GC)is the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide,with China bearing nearly half of the global burden[1,2].Most patients are diagnosed at stage Ⅲ–Ⅳ,and despite perioperative therapy plus D2 gastrectomy being the standard of care,long-term survival remains poor[3,4].展开更多
Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)predisposition syndrome,characterized by a high mutational burden and microsatellite instability-high(MSI-H)tumors.Immunology of LS-associated CRC(...Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)predisposition syndrome,characterized by a high mutational burden and microsatellite instability-high(MSI-H)tumors.Immunology of LS-associated CRC(LS-CRC)is unique,with significant implications for treatment.Despite well-established knowledge of LS immunology,immunotherapy dose and treatment response can vary significantly based on local tumor immunity and specific germline pathogenic variant of LS genes.This variability necessitates tailored surveillance strategies and new personalised immunotherapy approaches for LS patients.LS-CRC often benefits from immunotherapy due to the distinct tumor microenvironment(TME)and the variety of tumor infiltrating lymphocytes(TILs).This perspective discusses a novel approach of analysing spatial TILs at a single-cell level using tumor whole slide images(WSIs)that accounts for the distinct TME of LS-CRC.By emphasizing the necessity of personalized medicine in hereditary cancer syndromes,the future research and clinical practices that enhance patient outcomes through precision oncology is inspired.展开更多
基金supported by the postdoctoral fellowship program of CPSF(GZC20241270)the China Postdoctoral Science Foundation(2024M762496).
文摘Tumor cell-intrinsic programmed death-ligand 1(PD-L1)signals mediate tumor initiation,progression and metastasis,but their effects in ameloblastoma(AM)have not been reported.In this comprehensive study,we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates.Notably,we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT^(+)-AM cells,whereas genetic ablation of PD-L1 exerted opposing inhibitory effects.By performing highresolution single-cell profiling and thorough immunohistochemical analyses in AM patients,we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors.Our findings revealed that hTERT^(+)-AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial-mesenchymal transition.This phenotypic shift is induced by the activation of the PI3KAKT-mTOR signaling axis;thus,this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence.Importantly,targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patientderived tumor organoids,highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.
基金supported by the National Key Research and Development Program of China(2021YFA0910100 and 2022YFC2504602)Healthy Zhejiang One Million People Cohort(K-20230085)+9 种基金National Natural Science Foundation of China(82304946,82241230,T2125002,82341007,82304946,82473489,and 82573745)Zhejiang gastrointestinal cancer Clinical Medical Research Center(2022E50006)Medical Science and Technology Project of Zhejiang Province(WKJ-ZJ-2323)Beijing Natural Science Foundation(Z220014)Natural Science Foundation of Zhejiang Province(LR21H280001,LBZ22H160002,LBD24H290001,and LMS25H160006)Science and Technology Projects of Zhejiang Province(2019C03049)Program of Zhejiang Provincial TCM Sci-tech Plan(2018ZY006 and 2020ZZ005)Science and Technology Projects of Zhejiang Province(2022KY684)Program of Zhejiang Provincial TCM Sci-tech Plan(2022ZQ020)the New Cornerstone Science Foundation through the XPLORER PRIZE.
文摘Gastric cancer(GC)is the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide,with China bearing nearly half of the global burden[1,2].Most patients are diagnosed at stage Ⅲ–Ⅳ,and despite perioperative therapy plus D2 gastrectomy being the standard of care,long-term survival remains poor[3,4].
文摘Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)predisposition syndrome,characterized by a high mutational burden and microsatellite instability-high(MSI-H)tumors.Immunology of LS-associated CRC(LS-CRC)is unique,with significant implications for treatment.Despite well-established knowledge of LS immunology,immunotherapy dose and treatment response can vary significantly based on local tumor immunity and specific germline pathogenic variant of LS genes.This variability necessitates tailored surveillance strategies and new personalised immunotherapy approaches for LS patients.LS-CRC often benefits from immunotherapy due to the distinct tumor microenvironment(TME)and the variety of tumor infiltrating lymphocytes(TILs).This perspective discusses a novel approach of analysing spatial TILs at a single-cell level using tumor whole slide images(WSIs)that accounts for the distinct TME of LS-CRC.By emphasizing the necessity of personalized medicine in hereditary cancer syndromes,the future research and clinical practices that enhance patient outcomes through precision oncology is inspired.
