LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma
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<sup>+</sup> T cells conferred cytotoxic activity against a panel of HLA-A*02:01<sup>+</sup> 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.
Authors
- Beatriz M. Carreno (ORCID: https://orcid.org/0000-0002-8123-2035)
- Carl H. June (ORCID: https://orcid.org/0000-0003-0241-3557)
- Reyaz ur Rasool (ORCID: https://orcid.org/0009-0001-5530-682X)
- Tatiana Blanchard
- Pouya Faridi (ORCID: https://orcid.org/0000-0002-2712-3356)
- Grace Huang
- Gerald P. Linette (ORCID: https://orcid.org/0000-0001-6147-6115)
- Avery D. Posey (ORCID: https://orcid.org/0000-0001-8711-629X)
- Khatuna Gabunia
- Adham S. Bear (ORCID: https://orcid.org/0000-0002-3137-449X)
- Anthony W. Purcell (ORCID: https://orcid.org/0000-0003-0532-8331)
- Rochelle Ayala (ORCID: https://orcid.org/0000-0001-8538-8857)
- Irfan A. Asangani (ORCID: https://orcid.org/0000-0001-5381-1702)
- John Scholler (ORCID: https://orcid.org/0000-0002-9725-6277)
- Mei Ji (ORCID: https://orcid.org/0000-0003-0116-3074)
- Terry Lim
- Chong Xu
Institutions
- Cancer Research Institute (US)
- Australian Regenerative Medicine Institute (AU)
- Hudson Institute of Medical Research (AU)
- Parker Institute for Cancer Immunotherapy (US)
- Translational Therapeutics (United States) (US)
- Philadelphia VA Medical Center (US)
- Monash University (AU)
- University of Pennsylvania (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1038/s41598-025-96877-9
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Cancer Society
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Sarcoma Foundation of America
- University of Pennsylvania
- Victorian Cancer Agency
- Australian Lions Childhood Cancer Research Foundation
- Parker Institute for Cancer Immunotherapy
- Australian Government
- Abramson Cancer Center
- Cancer Australia
- National Institutes of Health
- National Health and Medical Research Council