Driver mutation landscape of acute myeloid leukemia provides insights for neoantigen-based immunotherapy

• Published in: Cancer letters 2024-12, Vol.611, p.217427, Article 217427
• Main Authors: Jin, Peng, Shen, Jie, Zhao, Ming, Yu, Jinyi, Jin, Wen, Jiang, Ge, Li, Zeyi, He, Mengke, Liu, Xiaxin, Wu, Shishuang, Dong, Fangyi, Cao, Yuncan, Zhu, Hongming, Li, Xiaoyang, Wang, Xiaoling, Zhang, Yunxiang, Jin, Zhen, Wang, Kankan, Li, Junmin
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; epitope immunogenicity; immunosuppressive milieu; neoantigen; T cell exhaustion
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.217427

Acute myeloid leukemia (AML) has lagged in benefiting from immunotherapies, primarily due to the scarcity of actionable AML-specific antigens. Driver mutations represent promising immunogenic targets, but a comprehensive characterization of the AML neoantigen landscape and their impact on patient outcomes and the AML immune microenvironment remain unclear. Herein, we conducted matched DNA and RNA sequencing on 304 AML patients and extensively integrated data from additional ∼2,500 AML cases, identifying 49 driver genes, notably characterized by a significant proportion of insertions and deletions (indels). Neoantigen analysis showed that indels triggered a higher abundance of neoantigens both in quantity and quality compared to single nucleotide variants (SNVs) and gene fusions. By integrating peptide features pertinent to neoantigen presentation and T cell recognition, we developed two robust models of epitope immunogenicity that significantly enriched immunogenic neoepitopes. We validated 30 neoantigens through in vitro direct binding assays of predicted peptides to MHC proteins and confirmed the immunogenicity of 20 neoantigens using interferon-γ ELISpot and tetramer assays. Moreover, we demonstrated that patients with higher neoantigen loads, derived from driver mutations, exhibited poor clinical outcomes and an IFN-driven adaptive immune response, which was associated with immune suppression and tumor evasion. Through deconvolution of large-scale bulk transcriptomes, integration of single-cell RNA sequencing and multiparametric flow cytometry, we confirmed a strong association between neoantigen load and CD8+ T cell exhaustion. This study provides a comprehensive landscape of AML neoantigens derived from driver mutations, offering putative immunogenic targets and emphasizing the need for strategies to revitalize the immunosuppressive milieu. •Comprehensive analysis identifies a high prevalence of indel mutations among AML driver variants•Indels generate more abundant and higher-quality neoantigens than SNVs and fusions.•Two models developed to enrich for highly immunogenic neoepitopes in AML•Neoantigen load is linked to CD8+ T cell exhaustion and poor patient outcomes