Unraveling the surface proteomic profile of multiple myeloma to reveal new immunotherapeutic targets and markers of drug resistance.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2022-11-01 DOI:10.15698/cst2022.11.273
Bonell Patiño-Escobar, Ian D Ferguson, Arun P Wiita
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引用次数: 2

Abstract

The cell surface proteome ("surfaceome") serves as the interface between diseased cells and their local microenvironment. In cancer, this compartment is critical not only for defining tumor biology but also serves as a rich source of potential therapeutic targets and diagnostic markers. Recently, we profiled the surfaceome of the blood cancer multiple myeloma, an incurable plasma cell malignancy. While available small molecule agents can drive initial remissions in myeloma, resistance inevitably occurs. Several new classes of immunotherapies targeting myeloma surface antigens, including antibody therapeutics and chimeric antigen receptor (CAR) T-cells, can further prolong survival. However, new approaches are still needed for those who relapse. We thus applied the glycoprotein cell surface capture (CSC) methodology to panel of multiple myeloma cell lines, identifying key surface protein features of malignant plasma cells. We characterized the most abundant surface proteins on plasma cells, nominating CD48 as a high-density antigen favorable for a possible avidity-based strategy to enhance CAR-T efficacy. After chronic resistance to proteasome inhibitors, a first-line therapy, we found significant alterations in the surface profile of myeloma cells, including down-regulation of CD50, CD361/EVI2B, and CD53, while resistance to another first-line therapy, lenalidomide, drove increases in CD33 and CD45/PTPRC. In contrast, short-term treatment with lenalidomide led to upregulation of the surface antigen MUC-1, thereby enhancing efficacy of MUC-1 targeting CAR-T cells. Integrating our proteomics data with available transcriptome datasets, we developed a scoring system to rank potential standalone immunotherapy targets. Novel targets of interest included CCR10, TXNDC11, and LILRB4. We developed proof-of-principle CAR-T cells versus CCR10 using its natural ligand, CCL27, as an antigen recognition domain. Finally, we developed a "miniaturized" version of the CSC methodology and applied it to primary myeloma patient specimens. Overall, our work creates a unique resource for the myeloma community. This study also supports unbiased surface proteomic profiling as a fruitful strategy for identifying new therapeutic targets and markers of drug resistance, that could have utility in improving myeloma patient outcomes. Similar approaches could be readily applied to additional tumor types or even models/tissues derived from other diseases.

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揭示多发性骨髓瘤的表面蛋白质组学特征,揭示新的免疫治疗靶点和耐药性标记。
细胞表面蛋白质组(“表面组”)作为患病细胞与其局部微环境之间的界面。在癌症中,这个隔室不仅对肿瘤生物学的定义至关重要,而且也是潜在治疗靶点和诊断标志物的丰富来源。最近,我们分析了血癌多发性骨髓瘤的表面组织,这是一种无法治愈的浆细胞恶性肿瘤。虽然现有的小分子药物可以缓解骨髓瘤,但不可避免地会出现耐药性。几种新的针对骨髓瘤表面抗原的免疫疗法,包括抗体疗法和嵌合抗原受体(CAR) t细胞,可以进一步延长生存期。然而,对于那些复发的人,仍然需要新的方法。因此,我们将糖蛋白细胞表面捕获(CSC)方法应用于多发性骨髓瘤细胞系面板,确定恶性浆细胞的关键表面蛋白特征。我们表征了浆细胞上最丰富的表面蛋白,提名CD48作为高密度抗原,有利于可能的基于亲和力的策略来增强CAR-T疗效。在对蛋白酶体抑制剂(一种一线治疗)慢性耐药后,我们发现骨髓瘤细胞表面谱发生了显著变化,包括CD50、CD361/EVI2B和CD53的下调,而对另一种一线治疗来那度胺的耐药则导致CD33和CD45/PTPRC的增加。相比之下,来那度胺短期治疗导致表面抗原MUC-1上调,从而增强了MUC-1靶向CAR-T细胞的疗效。整合我们的蛋白质组学数据和可用的转录组数据集,我们开发了一个评分系统来对潜在的独立免疫治疗靶点进行排名。新的靶点包括CCR10、TXNDC11和LILRB4。我们利用CCR10的天然配体CCL27作为抗原识别结构域,开发了CAR-T细胞对抗CCR10的原理验证。最后,我们开发了CSC方法的“小型化”版本,并将其应用于原发性骨髓瘤患者标本。总的来说,我们的工作为骨髓瘤社区创造了一个独特的资源。该研究还支持无偏见的表面蛋白质组学分析作为一种有效的策略,用于确定新的治疗靶点和耐药标记,这可能有助于改善骨髓瘤患者的预后。类似的方法可以很容易地应用于其他肿瘤类型甚至来自其他疾病的模型/组织。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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