Immunotherapeutic targeting of surfaceome heterogeneity in AML. Immunotherapeutic targeting of surfaceome heterogeneity in AML

Immunotherapy remains underexploited in AML compared to other hematological malignancies. Currently, gemtuzumab ozogamicin is the only therapeutic antibody approved for this disease. To identify potential targets for immunotherapeutic intervention, we analyzed the surface proteome of 100 genetically diverse primary human AML specimens for the identification of cell surface proteins and conducted single-cell transcriptome analysis on a subset of these specimens to assess antigen expression at the sub-population level. Through this comprehensive effort, we successfully identified numerous antigens and markers preferentially expressed by primitive AML cells. Many identified antigens are targeted by therapeutic antibodies currently under clinical evaluation for various cancer types, highlighting the potential therapeutic value of the approach. Importantly, this initiative led to the uncovering of AML heterogeneity at the surfaceome level, identifying several antigens and potential LSC markers characterising AML subgroups and positioning immunotherapy as a promising approach to target AML subgroup specificities. Overall design: Single-cell RNA sequencing of 20 primary human AML specimens for antigen and marker identification

与其他血液系统恶性肿瘤相比，急性髓系白血病（Acute Myeloid Leukemia, AML）领域的免疫治疗仍未得到充分开发。目前，吉妥珠单抗奥唑米星（gemtuzumab ozogamicin）是唯一获批用于该病的治疗性抗体。
为鉴定免疫治疗干预的潜在靶点，本研究对100份具有遗传异质性的原代人AML标本的细胞表面蛋白质组开展分析，以鉴定细胞表面蛋白；同时对其中部分标本实施单细胞转录组分析，以评估抗原在细胞亚群层面的表达特征。
通过此项系统性研究，我们成功鉴定出大量优先在原始AML细胞中表达的抗原与标志物。诸多已鉴定的抗原已成为多种癌症类型临床在研治疗性抗体的靶点，这凸显了本研究策略的潜在治疗价值。
尤为关键的是，本研究揭示了AML在表面组（surfaceome）层面的异质性，鉴定出数种可表征AML亚群的抗原及潜在白血病干细胞（Leukemia Stem Cell, LSC）标志物，并确立了免疫治疗作为靶向AML亚群特异性的极具前景的治疗策略。
整体实验设计：对20份原代人AML标本开展单细胞RNA测序，用于抗原与标志物的鉴定。