研究动态
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开发人类胰腺癌化身作为动态免疫景观分析和个性化治疗的模型。

Development of human pancreatic cancer avatars as a model for dynamic immune landscape profiling and personalized therapy.

发表日期:2024 Jul 05
作者: Daniel Hughes, Alice Evans, Simei Go, Michael Eyres, Liuliu Pan, Somnath Mukherjee, Zahir Soonawalla, Frances Willenbrock, Eric O'Neill
来源: CLINICAL PHARMACOLOGY & THERAPEUTICS

摘要:

胰腺导管腺癌(PDAC)是胰腺癌最常见的形式,这种疾病的总体生存率很低。缺乏临床前模型阻碍了治疗的进展。在这里,我们展示了如何从切除的组织中创建个性化的器官型“化身”,从而能够对完整的原位肿瘤微环境进行空间和时间报告,并反映临床反应。我们的灌注培养方法延长了肿瘤切片的活力,维持稳定的肿瘤内容、代谢、基质成分和免疫细胞群长达 12 天。使用多重免疫荧光和空间转录组学,我们确定了免疫邻域和免疫治疗的潜力。我们使用化身来评估临床前验证的代谢疗法的影响,并显示基质和免疫表型的恢复以及肿瘤的再分化。为了确定临床相关性,我们监测了化身对吉西他滨治疗的反应,并从临床随访中确定了患者化身可预测的反应。因此,化身为治疗方法的同基因测试提供了有价值的信息,并为患者提供了真正个性化的治疗评估平台。
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, a disease with dismal overall survival. Advances in treatment are hindered by a lack of preclinical models. Here, we show how a personalized organotypic "avatar" created from resected tissue allows spatial and temporal reporting on a complete in situ tumor microenvironment and mirrors clinical responses. Our perfusion culture method extends tumor slice viability, maintaining stable tumor content, metabolism, stromal composition, and immune cell populations for 12 days. Using multiplexed immunofluorescence and spatial transcriptomics, we identify immune neighborhoods and potential for immunotherapy. We used avatars to assess the impact of a preclinically validated metabolic therapy and show recovery of stromal and immune phenotypes and tumor redifferentiation. To determine clinical relevance, we monitored avatar response to gemcitabine treatment and identify a patient avatar-predictable response from clinical follow-up. Thus, avatars provide valuable information for syngeneic testing of therapeutics and a truly personalized therapeutic assessment platform for patients.