CBFB-MYH11 fusion neoantigen enables T cell recognition and killing of acute myeloid leukemia
CBFB-MYH11 fusion neoantigen enables T cell recognition and killing of acute myeloid leukemia
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DOI：
10.1172/jci137723
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发表时间：
2020-10-01
影响因子：
15.9
通讯作者：
Bleakley, Marie
中科院分区：
文献类型：
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作者：
Biernacki, Melinda A.;Foster, Kimberly A.;Bleakley, Marie
由Cbfb-MYH11等反复融合基因产生的蛋白质普遍存在于急性髓系白血病(AML)中，这种蛋白通常是白血病发生所必需的，在整个病程中持续存在，并且具有高度的白血病特异性，使它们成为免疫治疗的新抗原靶点。从流行的Cbfb-MYH11融合蛋白中提取的一种非序列多肽在HLA-B*40：01*捐赠者中被发现具有免疫原性。从健康供者分离的高亲和力CD8(+)T细胞克隆在体外对Cbfb-MYHir HLAB*40：01(+)AML细胞株和原代人AML标本具有杀伤作用。在患者来源的小鼠异种移植模型中，Cbfb-MYH11特异性T细胞也在体内控制Cbfb-MYH11(+)人类白细胞抗原-B*40：01(+)AML。高亲和力CBFBM-YH11表位特异性T细胞受体(TCR)转导CO8。T细胞在体外具有抗白血病活性。我们的数据表明，Cbfb-MYH11融合新抗原自然存在于AML原始细胞上，并能识别和杀伤AML的T细胞。我们提供了免疫靶向AML启动融合的原理证据，并证明了靶向新抗原具有临床意义，即使在融合驱动的AML等低突变频率的癌症中也是如此。这项工作也代表了针对融合基因驱动的AML的TCRT细胞免疫治疗发展的第一个关键步骤。
Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01* donors. High-avidity CD8(+) T cell clones isolated from healthy donors killed CBFB-MYHir HLA-B*40:01(+) AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11(+) HLA-B*40:01(+) AML in vivo in a patient-derived murine xenograft model. High-avidity CBFBM-YH11 epitope-specific T cell receptors (TCRs) transduced into CO8 . T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.