Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin

Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.

癌症中的体细胞突变是癌症特异性新抗原（neoantigen）的潜在来源。急性髓系白血病（AML）除存在个体特异性私有突变外，还存在患者间共有的复发性常见突变。本研究提出假说：源自复发性共有突变的新抗原有望成为未来免疫治疗策略的理想靶点。本研究采用质谱技术，对13例原发性AML肿瘤样本与2株AML细胞系（OCI-AML3、MV4-11）的人类白细胞抗原（HLA）I类与II类免疫肽组进行分析，以探究源自AML常见共有突变的内源性携带突变的HLA配体。本研究从核仁磷酸蛋白（NPM1）中鉴定出2种内源性携带突变的HLA I类配体：分别来自2例患者样本的AVEEVSLRK，以及来自OCI-AML3的C(半胱氨酸)LAVEEVSL。二者分别被预测可结合常见HLA单倍型HLA-A*03:01与HLA-A*02:01。鉴于约三分之一的AML患者存在NPM1突变，此次从突变型NPM1中鉴定出内源性HLA配体的发现，可为针对该共有靶点的免疫治疗策略相关后续研究提供支持，惠及此类AML患者亚群。