Abstract B010: Immunoediting of fusion-positive rhabdomyosarcoma after NK cell-based immunotherapy

Abstract Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma with skeletal muscle characteristics in children and adolescents. Among its subtypes, fusion-positive RMS (FP-RMS) is defined by a chromosomal translocation that encodes a fusion oncoprotein, most commonly PAX3::FOXO1 or PAX7::FOXO1. FP-RMS has a weaker response to conventional radiation and chemotherapy, with a 5-year survival rate of only 20–30% in patients with metastatic disease. Natural killer (NK) cell–based therapy has emerged as a promising strategy in cancer immunotherapy, offering a potentially safer, "off-the-shelf" alternative to T-cell therapies as it does not mediate graft-versus-host disease (GVHD). NK cells can recognize and eliminate malignant cells, including FP-RMS, without prior sensitization. However, the long-term success of NK therapies will largely depend on their durability. A key challenge in the field is that it is unclear whether RMS cells would adapt and eventually resist NK cell attack, which could ultimately undermine therapeutic effectiveness.To address this question, we investigated how RMS cells respond to primary human NK cells using cytotoxicity assays and flow cytometry. We found that prolonged NK cell exposure induces an immunoedited state in RMS cells—a process by which tumor cells adapt under immune pressure, leading to the selection of variants with reduced immunogenicity and increased resistance to immune attack. We hypothesize that this immunoedited state represents a stable epigenetic program associated with enhanced resistance to subsequent NK-mediated killing. Phenotypically, this adaptive response includes upregulation of HLA-ABC and HLA-E, which engage inhibitory NK receptors that dampen NK cell cytotoxicity. Concurrent upregulation of PD-L1 on RMS cells further contributes to immune suppression by inhibiting NK effector functions through the PD-1 axis. Future work will include studies to define the transcriptional and epigenetic programs driving this adaptive response. These findings identify a potential mechanism of RMS immune evasion and highlight potential therapeutic opportunities such as blockade of NKG2A or PD-1 pathways to restore anti-tumor immunity and overcome resistance. Citation Format: Zhiyu Song, Benjamin Stanton, Dean Lee. Immunoediting of fusion-positive rhabdomyosarcoma after NK cell-based immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr B010.