LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma
Abstract Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the pathognomonic EWSR1::FLI1 fusion. Recent reports indicate that the EWSR1::FLI1 oncofusion drives aberrant expression of numerous transcripts, including Lipoxygenase...
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Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-96877-9 |
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| author | Tatiana Blanchard Pouya Faridi Chong Xu Adham S. Bear Reyaz ur Rasool Grace Huang Terry C. C. Lim Rochelle Ayala Khatuna Gabunia Mei Ji Avery D. Posey John Scholler Irfan A. Asangani Anthony W. Purcell Gerald P. Linette Carl H. June Beatriz M. Carreno |
| author_facet | Tatiana Blanchard Pouya Faridi Chong Xu Adham S. Bear Reyaz ur Rasool Grace Huang Terry C. C. Lim Rochelle Ayala Khatuna Gabunia Mei Ji Avery D. Posey John Scholler Irfan A. Asangani Anthony W. Purcell Gerald P. Linette Carl H. June Beatriz M. Carreno |
| author_sort | Tatiana Blanchard |
| collection | DOAJ |
| description | Abstract Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the pathognomonic EWSR1::FLI1 fusion. Recent reports indicate that the EWSR1::FLI1 oncofusion drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOXHD1). Given its highly restricted protein expression pattern and role in EwS tumorigenesis and metastasis, LOXHD1 may serve as a novel immunotherapeutic target in this malignancy. LOXHD1 immunogenic epitopes restricted to HLA-A*02:01 allowed for the isolation of a high avidity αβTCR. LOXHD1-specific TCR engineered CD8+ T cells conferred cytotoxic activity against a panel of HLA-A*02:01+ EwS tumor cell lines and adoptive transfer led to tumor eradication in a mouse xenograft model of EwS. This study nominates LOXHD1 as an oncofusion regulated, non-mutated tumor associated antigen (TAA) with expression limited to inner hair cells of the cochlea, adult testis, and EwS. |
| format | Article |
| id | doaj-art-71ede091145a4392a1a07eed8a28b41d |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-71ede091145a4392a1a07eed8a28b41d2025-08-20T02:17:47ZengNature PortfolioScientific Reports2045-23222025-04-0115111310.1038/s41598-025-96877-9LOXHD1 is an oncofusion-regulated antigen of ewing sarcomaTatiana Blanchard0Pouya Faridi1Chong Xu2Adham S. Bear3Reyaz ur Rasool4Grace Huang5Terry C. C. Lim6Rochelle Ayala7Khatuna Gabunia8Mei Ji9Avery D. Posey10John Scholler11Irfan A. Asangani12Anthony W. Purcell13Gerald P. Linette14Carl H. June15Beatriz M. Carreno16Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaCentre for Cancer Research, Hudson Institute of Medical Research, Monash UniversityCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaDivision of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, BRBII/IIICentre for Cancer Research, Hudson Institute of Medical Research, Monash UniversityCentre for Cancer Research, Hudson Institute of Medical Research, Monash UniversityDepartment of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash UniversityCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, BRBII/IIIDepartment of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash UniversityCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaCenter for Cellular Immunotherapies, Perelman School of Medicine, University of PennsylvaniaAbstract Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the pathognomonic EWSR1::FLI1 fusion. Recent reports indicate that the EWSR1::FLI1 oncofusion drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOXHD1). Given its highly restricted protein expression pattern and role in EwS tumorigenesis and metastasis, LOXHD1 may serve as a novel immunotherapeutic target in this malignancy. LOXHD1 immunogenic epitopes restricted to HLA-A*02:01 allowed for the isolation of a high avidity αβTCR. LOXHD1-specific TCR engineered CD8+ T cells conferred cytotoxic activity against a panel of HLA-A*02:01+ EwS tumor cell lines and adoptive transfer led to tumor eradication in a mouse xenograft model of EwS. This study nominates LOXHD1 as an oncofusion regulated, non-mutated tumor associated antigen (TAA) with expression limited to inner hair cells of the cochlea, adult testis, and EwS.https://doi.org/10.1038/s41598-025-96877-9 |
| spellingShingle | Tatiana Blanchard Pouya Faridi Chong Xu Adham S. Bear Reyaz ur Rasool Grace Huang Terry C. C. Lim Rochelle Ayala Khatuna Gabunia Mei Ji Avery D. Posey John Scholler Irfan A. Asangani Anthony W. Purcell Gerald P. Linette Carl H. June Beatriz M. Carreno LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma Scientific Reports |
| title | LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma |
| title_full | LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma |
| title_fullStr | LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma |
| title_full_unstemmed | LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma |
| title_short | LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma |
| title_sort | loxhd1 is an oncofusion regulated antigen of ewing sarcoma |
| url | https://doi.org/10.1038/s41598-025-96877-9 |
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