The association of neurogenesis and gliogenesis with glioma remains unclear.By conducting single-cell RNA-seq analyses on 26 gliomas,we reported their classification into primitive oligodendrocyte precursor cell(pri-O...The association of neurogenesis and gliogenesis with glioma remains unclear.By conducting single-cell RNA-seq analyses on 26 gliomas,we reported their classification into primitive oligodendrocyte precursor cell(pri-OPC)-like and radial glia(RG)-like tumors and validated it in a public cohort and TCGA glioma.The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations,and the pri-OPC-like ones were prone to carrying TP53 mutations.Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes,suggesting their distinct immune evasion programs.Furthermore,the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners.Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes.For example,glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes,respectively.Their expression was positively correlated with those of immune checkpoint genes(e.g.,LGALS33)and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells.This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.展开更多
Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking ...Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking tumors5 immune evasion will re-activate the host immune systems to eliminate tumors.Immune-checkpoint therapy(ICT)which applies anti-PD-l/PD-Ll or anti-CTLA4 treatment has been a remarkable success in the past few years.However,〜70%of patients cannot gain any clinical benefits from ICT treatment due to the tumorimmunity system's complexity・In the past,germline pathogenic variants have been thought to have only minorheritable contributions to cancer.Results:Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system.The functional components of the immune system are encoded by the host genome,thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response.Indeed,recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by(i)shaping tumor somatic mutations,altering methylation patterns and antigen-presentation capacity or(ii)influencing NK cell's function to modulate lymphocyte infiltration in the tumor microenvironment.In addition,the HLA(types A,B or C)genotypes also shape the landscape of tumor somatic mutations.Conclusion:These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.展开更多
基金supported by talent startup funding from Fudan University(Nos.JIF101017,SXF101012,and JIF101047)Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Project(No.2021ZD0201100 Task 4 and No.2021ZD0201104)from the Ministry of Science and Technology(MOST),China+3 种基金Jinsong Wu was supported by Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)ZJ Lab,and operating grant of Shanghai Brain Bank technical system(No.16JC1420103)Edwin Wang was supported by Alberta Innovates Translational Chair Program in Cancer Genomics,the Natural Sciences and Engineering Research Council of Canada(NSERC,No.RGPIN-2017-04885)Canadian Foundation of Innovation(No.36655).
文摘The association of neurogenesis and gliogenesis with glioma remains unclear.By conducting single-cell RNA-seq analyses on 26 gliomas,we reported their classification into primitive oligodendrocyte precursor cell(pri-OPC)-like and radial glia(RG)-like tumors and validated it in a public cohort and TCGA glioma.The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations,and the pri-OPC-like ones were prone to carrying TP53 mutations.Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes,suggesting their distinct immune evasion programs.Furthermore,the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners.Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes.For example,glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes,respectively.Their expression was positively correlated with those of immune checkpoint genes(e.g.,LGALS33)and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells.This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.
文摘Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking tumors5 immune evasion will re-activate the host immune systems to eliminate tumors.Immune-checkpoint therapy(ICT)which applies anti-PD-l/PD-Ll or anti-CTLA4 treatment has been a remarkable success in the past few years.However,〜70%of patients cannot gain any clinical benefits from ICT treatment due to the tumorimmunity system's complexity・In the past,germline pathogenic variants have been thought to have only minorheritable contributions to cancer.Results:Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system.The functional components of the immune system are encoded by the host genome,thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response.Indeed,recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by(i)shaping tumor somatic mutations,altering methylation patterns and antigen-presentation capacity or(ii)influencing NK cell's function to modulate lymphocyte infiltration in the tumor microenvironment.In addition,the HLA(types A,B or C)genotypes also shape the landscape of tumor somatic mutations.Conclusion:These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.
