CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Pancreatic Cancer Organoids Recapitulate Chemotherapy Response and Identify a Potent Cytotoxic T-Cell Population.
Pancreatic Cancer Organoids Recapitulate Chemotherapy Response and Identify a Potent Cytotoxic T-Cell Population.
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我们证实了在临床相关时间范围内生成 PDOs 的可行性，并提供了证据表明其在推动 PDAC 治疗成功方面的实用性。
胰腺导管腺癌（PDAC）不理想的治疗结局凸显了确定精准治疗方式的必要性。我们旨在利用患者来源类器官（PDO）来预测潜在联合治疗中最有效的单个组分。
自胰腺导管腺癌（PDAC）切除组织中建立了自体富集TIL（肿瘤浸润淋巴细胞）和PDO培养物。通过免疫染色、靶向下一代测序以及采用标准治疗多药化疗方案进行的药物筛选对PDO进行了表征。通过流式细胞术、测序以及针对自体PDO的效力分析对扩增的TIL培养物进行了分析。
PDO培养以80%的成功率建立。除了忠实地再现亲本肿瘤的分子和组织学特征外，PDO在36天的临床相关时间范围内充分扩增以进行药物分型。值得注意的是，PDO化疗敏感性谱与患者血清CA 19-9动态变化和无复发生存期相关。此外，扩增富集的TIL支持TCR+细胞的激活，并针对自体PDO靶标表现出更强大的功能。重要的是，胰腺肿瘤组织内T细胞的浸润与总生存期改善相关。
Unsatisfactory outcomes in pancreatic ductal adenocarcinoma (PDAC) highlight the need to identify precision-based treatment modalities. We aimed to utilize patient-derived organoids (PDO) to predict the most effective individual components of potential combination therapies. EXPERIMENTAL DESIGN: Autologous - and -enriched tumor-infiltrating lymphocyte (TIL) and PDO cultures were established from resected PDAC tissue. PDOs were characterized by immunostaining, targeted next-generation sequencing, and drug screening with standard-of-care multidrug chemotherapeutic regimens. Expanded TIL cultures were profiled through flow cytometry, sequencing, and potency against autologous PDOs.
PDO cultures were established with an 80% success rate. In addition to faithfully recapitulating molecular and histologic features of the parental tumor, PDOs were sufficiently expanded for pharmacotyping within a clinically relevant time frame of 36 days. Notably, PDO chemotherapeutic sensitivity profiles correlated with patient serum CA 19-9 dynamics and recurrence-free survival. Furthermore, expanded -enriched TILs supported the activation of TCR+ cells and demonstrated more potent functionality in response to autologous PDO targets. Importantly, infiltration of T cells within pancreatic tumor tissue was associated with improved overall survival.
We confirm the feasibility of generating PDOs within a clinically relevant time frame and provide evidence of their utility for advancing therapeutic success in PDAC.
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