Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful...Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity.Here,we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ.Both C/EBPβand RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks.We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4.This epitope was validated for its ability to stimulate T cell responses in HLA-A24^(+)donors and GBM patients,leading us to identify RCAN1-4-reactive T cell receptors(TCRs)for the construction of TCR-engineered T cells(TCR-T cells).Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells,highlighting its potential as an immunotherapeutic target in mesenchymal GBM.展开更多
基金supported by the Botha-Chan Research Fund,the Office of the Assistant Secretary of Defense for Health Affairs through award no.HT9425-24-1-0623(I.R.)the Brain Tumor Funders'Collaborative,the Ellie Kavalieros DIPG Research Fund+6 种基金the UPMC Children’s Hospital of Pittsburgh Foundation(G.K.,I.R.)the Children’s Brain Tumor Network(I.F.P.),a stipend from the Central South University Xiangya School of Medicine and University of Pittsburgh(Z.X.)by grant NS117742 from the National Institute of Health(T.G.F.)support from the Jesse H.&Mary Jones Gibbs Endowed Chair(T.G.F)supported in part by the University of Pittsburgh Center for Research Computing,RRID:SCR_022735through NIH award number S10OD028483Work performed in the UPMC Hillman Cancer Center Tissue and Research Pathology Services Shared Resource Facility and the services and instruments used in this project were supported,in part,by the University of Pittsburgh and the NCI of the NIH under Award Number P30CA047904.
文摘Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity.Here,we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ.Both C/EBPβand RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks.We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4.This epitope was validated for its ability to stimulate T cell responses in HLA-A24^(+)donors and GBM patients,leading us to identify RCAN1-4-reactive T cell receptors(TCRs)for the construction of TCR-engineered T cells(TCR-T cells).Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells,highlighting its potential as an immunotherapeutic target in mesenchymal GBM.
