CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids
CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids
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DOI：
10.1186/s40425-019-0575-3
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发表时间：
2019-04-15
影响因子：
10.9
通讯作者：
Gerlinger, Marco
中科院分区：
文献类型：
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作者：
Gonzalez-Exposito, Reyes;Semiannikova, Maria;Gerlinger, Marco
背景：T细胞双特异性抗体CiBisatamab(CEA-TCB)结合癌细胞上的癌胚抗原(CEA)和T细胞上的CD3，从而触发T细胞杀伤在细胞表面表达中、高水平CEA的癌细胞系。患者来源的结直肠癌器官样物质(PDO)可能比已建立的细胞系更准确地代表患者肿瘤，这可能使我们能够更详细地了解CiBisatamab耐药和敏感性的机制。方法：我们从多药耐药的转移性癌细胞建立PDO。结果：根据细胞表面CEA的表达，PDO可分为3组：CEA(Hi)(n=3)、CEA(10)(n=1)和CEA(混合)pDO(n=4)，稳定维持CEA(Hi)和CEA(10)细胞群，这是以前在CRC细胞系中没有描述过的。CEA(Hi)、PDO敏感，而CEA(10)PDO对西比沙坦耐药。混合表达的PDO对CiBisatamab的敏感性较低，提示CEA(10)细胞维持癌细胞生长。从混合表达CEA的PDO中培养FACS分选的CEA(HI)和CEA(10)细胞，显示出CEA表达的高度可塑性，有助于通过CEA抗原丢失获得耐药性。RNA测序显示CEA(10)细胞中WNT/β-连环蛋白途径活性增加。结论：基于这些临床前的研究结果，CEA表达的异质性和可塑性似乎赋予了PDO较低的CiBisatamab敏感性，支持进一步的临床评估它们在结直肠癌中的预测作用。药物抑制WNT/β-catenin通路可能是使PCCs对ciBisatamab增敏的合理组合。我们新颖的PDO和T细胞共培养免疫治疗模型使临床前能够发现候选生物标记物和联合疗法，这些可能会通知和加速免疫肿瘤学药物在临床上的发展。
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(hi) (n = 3), CEA(10) (n = 1) and CEA(mixed) PDOs (n = 4), that stably maintained populations of CEA(hi), and CEA(10), cells, which has not previously been described in CRC cell lines. CEA(hi), PDOs were sensitive whereas CEA(10) PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA(10) cells maintain cancer cell growth. Culture of FACS-sorted CEA(hi) and CEA(10 )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/beta-catenin pathway activity in CEA(10) cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/beta-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/beta-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.