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<p>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.</p>

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LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月15日

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  • 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 Jr,
  • John Scholler,
  • Irfan A. Asangani,
  • Anthony W. Purcell,
  • Gerald P. Linette,
  • Carl H. June,
  • Beatriz M. Carreno

摘要

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.