Department of Translational Medicine and Clinical Pharmacology, Boehringer-Ingelheim GmbH, Ingelheim am Rhein, Hesse, Germany.
Hematogenix, Chicago, Illinois, United States of America.
PLoS One. 2024 Nov 4;19(11):e0313026. doi: 10.1371/journal.pone.0313026. eCollection 2024.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.
受体酪氨酸激酶样孤儿受体 1（ROR1）是目前用于开发新型治疗方法的肿瘤靶点，例如抗体药物偶联物、嵌合抗原受体 T 细胞疗法等。这些新药的成功取决于根据 ROR1 肿瘤患病率、染色异质性和亚细胞定位等参数选择相关适应症。我们使用经过验证的用于免疫组织化学（IHC）和流式细胞术（FC）的抗体克隆来研究 ROR1 免疫表型，分析了来自 7 种血液恶性肿瘤和三阴性乳腺癌（TNBC）的 292 个肿瘤标本作为参考实体肿瘤适应症。ROR1 的患病率在不同的肿瘤类型中差异显著，所有慢性淋巴细胞白血病（n=48）和毛细胞白血病（n=14）的 FC 分析标本均显示 100%的 ROR1 阳性，范围分别为 1.1-99.8%和 0.8-62.1%。通过 IHC 分析的样本显示，在 44%的套细胞淋巴瘤肿瘤样本（n=27；阳性病例的 H 评分范围：10-285）中存在 ROR1 膜/细胞质阳性；在 30%的 TNBC（n=46；H 评分范围：1-200）中；在弥漫性大 B 细胞淋巴瘤（n=45；H 评分：40-250）中为 15%；在滤泡性淋巴瘤（n=34；H 评分：2-300）中为 11%。最后，通过 IHC 分析，所有急性髓细胞白血病（n=52）和大多数 T 细胞非霍奇金淋巴瘤（n=31/32）的测试样本均为 ROR1 阴性。总之，ROR1 在多种白血病和淋巴瘤中表现出肿瘤细胞表达谱的异质性，因此它是一个肿瘤靶点，需要不同的患者选择策略来开发新型治疗方法。
