CEA 表达异质性和可塑性使患者来源的结直肠癌细胞类器官对 CEA 靶向双特异性免疫治疗抗体 cibisatamab（CEA-TCB）产生耐药性。
CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids.
机构信息
Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
Gastrointestinal Cancer Unit, The Royal Marsden NHS Foundation Trust, London and Sutton, UK.
出版信息
J Immunother Cancer. 2019 Apr 15;7(1):101. doi: 10.1186/s40425-019-0575-3.
BACKGROUND
The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity.
METHODS
We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells.
RESULTS
PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA (n = 3), CEA (n = 1) and CEA PDOs (n = 4), that stably maintained populations of CEA and CEA cells, which has not previously been described in CRC cell lines. CEA PDOs were sensitive whereas CEA PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA cells maintain cancer cell growth. Culture of FACS-sorted CEA and CEA cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway.
CONCLUSIONS
Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.
背景
T 细胞双特异性抗体 cibisatamab（CEA-TCB）与癌细胞表面的癌胚抗原（CEA）和 T 细胞表面的 CD3 结合，触发 T 细胞杀伤表面表达中等到高水平 CEA 的癌细胞系。源自患者的结直肠癌细胞类器官（PDO）可能比已建立的细胞系更准确地代表患者肿瘤，从而使我们能够更详细地了解 cibisatamab 耐药和敏感的机制。
方法
我们从多药耐药转移性 CRC 中建立了 PDO。通过 FACS 确定 PDO 的 CEA 表达，通过共培养 PDO 和同种异体 CD8 T 细胞评估 cibisatamab 免疫治疗的敏感性。
结果
根据 CEA 细胞表面表达，PDO 可分为 3 组：CEA（n=3）、CEA（n=1）和 CEA PDO（n=4），它们稳定维持 CEA 和 CEA 细胞群体，这在 CRC 细胞系中尚未被描述过。CEA PDO 对 cibisatamab 敏感，而 CEA PDO 对 cibisatamab 耐药。混合表达的 PDO 对 cibisatamab 的敏感性低，表明 CEA 细胞维持癌细胞生长。从具有混合 CEA 表达的 PDO 中 FACS 分选 CEA 和 CEA 细胞进行培养，证明 CEA 表达具有高可塑性，通过 CEA 抗原丢失导致耐药性获得。RNA 测序显示 CEA 细胞中 WNT/β-catenin 途径活性增加。细胞表面 CEA 表达受 WNT/β-catenin 途径抑制剂上调。
结论
基于这些临床前发现，CEA 表达的异质性和可塑性似乎使 PDO 对 cibisatamab 的敏感性降低，支持进一步临床评估其在 CRC 中的预测作用。WNT/β-catenin 途径的药理学抑制可能是使 CRC 对 cibisatamab 敏感的合理组合。我们的新型 PDO 和 T 细胞共培养免疫治疗模型使临床前发现候选生物标志物和联合治疗成为可能，这可能为免疫肿瘤学药物的开发提供信息并加速其发展。
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