Liu Enze, Jaouadi Oumaima, Sharma Riya, Becker Nathan, Johnson Travis S, Sudha Parvathi, Chopra Vivek S, Zafar Faiza, Hamidi Habib, Pawlyn Charlotte, Suvannasankha Attaya, Abonour Rafat, Walker Brian A
Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana University, Indianapolis, IN, USA.
Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Genome Med. 2025 Jul 15;17(1):79. doi: 10.1186/s13073-025-01503-y.
Immunotherapy is now standard of care for multiple myeloma (MM), where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D (GPRC5D). However, additional novel targets are needed to counter tumor heterogeneity, therefore new strategies to identify additional targets are also required.
We utilized multi-omics data from two large datasets A framework that utilized prior knowledge of cell surface potential, expression in healthy organs, and expression level in MM cells was established to define novel immunotherapeutic targets. High confidence targets were prioritized for myeloma populations and subgroups, validated with flow cytometry and immunoblotting.
Novel population-level candidate targets such as ITGA4 and LAX1, as well as subtype-specific targets including ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), CD180 in hyperdiploidy, GPRC5D in 1q gain, and ADAM28 in biallelic TP53 samples were identified. Candidate target surface expression was validated by flow cytometry and CRISPR-Cas9 knock-out models. Sub-clonal differences in expression were noted, using single-cell RNA-seq data. Additionally, alternative splicing of existing immunotherapy targets, such as FCRL5, was noted as a potential mechanism of antigen loss.
Our study presents a methodology to identify novel candidate immunotherapy targets. We also use known genomic data to identify subtype-specific targets that could be used either as complementary or alternative targets to existing treatments. We show that immunotherapy targets can have heterogenous expression within a patient, which can affect treatment efficacy. Taken together, our study establishes a robust methodology to identify novel therapeutic targets in MM, revealing critical insights that will inform the development of current and next-generation immunotherapies.
免疫疗法现已成为多发性骨髓瘤（MM）的标准治疗方法，其中最常见的靶点是B细胞成熟抗原、CD38和G蛋白偶联受体C类第5组成员D（GPRC5D）。然而，需要额外的新靶点来应对肿瘤异质性，因此也需要新的策略来识别更多靶点。
我们利用了来自两个大型数据集的多组学数据，建立了一个利用细胞表面电位的先验知识、在健康器官中的表达以及在MM细胞中的表达水平的框架，以定义新的免疫治疗靶点。对骨髓瘤群体和亚组的高可信度靶点进行了优先排序，并通过流式细胞术和免疫印迹进行了验证。
确定了新的群体水平候选靶点，如整合素α4（ITGA4）和LAX1，以及亚型特异性靶点，包括t（4；14）中的ROBO3、t（14；16）中的CD109、t（11；14）中的CD20、超二倍体中的CD180、1q增益中的GPRC5D以及双等位基因TP53样本中的ADAM28。通过流式细胞术和CRISPR-Cas9敲除模型验证了候选靶点的表面表达。利用单细胞RNA测序数据发现了表达的亚克隆差异。此外，还注意到现有免疫治疗靶点（如FCRL5）的可变剪接是抗原丢失的潜在机制。
我们的研究提出了一种识别新的候选免疫治疗靶点的方法。我们还利用已知的基因组数据来识别亚型特异性靶点，这些靶点可作为现有治疗的补充或替代靶点。我们表明，免疫治疗靶点在患者体内可能具有异质性表达，这可能影响治疗效果。总之，我们的研究建立了一种强大的方法来识别MM中的新治疗靶点，揭示了将为当前和下一代免疫疗法的发展提供信息的关键见解。
