PO.TB10.18 · 肿瘤生物学
生物打印的多细胞微环境以加速胰腺癌免疫疗法的发现
Bioprinted multicellular microenvironments to accelerate immunotherapy discovery in pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
90%的胰腺癌（PC）患者死于该疾病[1]，因此有必要开发更有效的治疗方法。PC肿瘤的特点是致密的纤维化基质区域，其中含有复杂的、高度重塑的细胞外基质。这些纤维化区域创造了保护性生态位，促进生长并保护癌细胞免受治疗侵害[2]。这些区域与肿瘤内的其他免疫抑制成分一起，阻止针对癌细胞的强健免疫应答，限制了免疫疗法的疗效。
在临床前环境中准确建模纤维化微环境仍然具有挑战性。二维模型可以纳入多种细胞类型和细胞外基质，但无法复制肿瘤中存在的营养物和药物梯度。这些结构特征在研究免疫相互作用时尤为重要，因为在患者中T细胞往往在空间上被排除在肿瘤生态位之外[3]。此外，体内模型可能缺乏足够的免疫成分，使得剖析治疗的因果效应变得困难，并受到通量成本的限制。
我们展示了使用Inventia Life Science的RASTRUM™ Allegro生物打印机，纳入癌症、基质、免疫和微环境成分的3D体外共培养模型的开发和表征。我们研究了CAF在支持免疫逃逸中的作用，并分析了各种情境下癌细胞-T细胞的动态。使用单细胞RNA测序，我们表明这一具有生理相关性的系统能更好地模拟天然PC肿瘤，同时保持药物筛选的可扩展性。模块化设计有助于组合药物测试以及跨不同细胞群剖析治疗效果的机制。该模型将用于识别在体内更有效的联合疗法，简化临床前测试，尤其适用于免疫疗法和免疫调节剂。
参考文献 1. Stoffel EM, Brand RE, Goggins M. Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention. Gastroenterology. 2023 Apr;164(5):752-765.
2. Neesse A, Bauer CA, Öhlund D et al. Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut. 2019 Jan;68(1):159-171.
3. Carstens JL, Correa de Sampaio P, Yang D et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Comm. 2017 Apr 27;8:15095。
查看英文原文 English abstract
90% of pancreatic cancer (PC) patients succumb to the disease [1], necessitating development of more effective treatments. PC tumors are characterized by dense fibrotic stromal regions that contain complex, highly remodelled extracellular matrices. These fibrotic regions create protective niches promoting growth and shielding cancer cells from therapies [2]. These regions, along with other immunosuppressive elements within the tumor, prevent robust immune responses against the cancer cells, limiting immunotherapy efficacy.
Accurately modeling fibrotic microenvironments in preclinical settings remains challenging. Two-dimensional models can incorporate multiple cell types and extracellular matrices, but fail to replicate nutrient and drug gradients that exist in tumors. These architectural features are particularly important when studying immune interactions, as T cells are often spatially excluded from tumor niches in patients [3]. Furthermore, in vivo models can lack sufficient immune components, make dissecting causal effects of therapies difficult and are limited by throughput costs.
We present development and characterization of 3D in vitro co-culture models incorporating cancer, stroma, immune and microenvironment components using the RASTRUM TM Allegro bioprinter from Inventia Life Science. We investigate the role of CAFs in supporting immune evasion and analyze cancer-T cell dynamics in various contexts. Using single-cell RNA sequencing we show this physiologically-relevant system better mimics native PC tumors while maintaining scalability for drug screening. The modular design facilitates combinatorial drug testing and mechanistic dissection of therapy effects across distinct cell populations. This model will be utilised to identify combination therapies that are more effective in vivo, streamlining preclinical testing, particularly for immunotherapies and immunomodulators.
References 1. Stoffel EM, Brand RE, Goggins M. Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention. Gastroenterology. 2023 Apr;164(5):752-765.
2. Neesse A, Bauer CA, Öhlund D et al. Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut. 2019 Jan;68(1):159-171.
3. Carstens JL, Correa de Sampaio P, Yang D et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Comm. 2017 Apr 27;8:15095.
利益披露 Disclosure
A. McCorkindale, None..
S. Lombardi, None..
I. Navarro, None..
D. Chacon Fajardo, None..
H. Barraclough-Franks, None..
D. Hermann, None..
S. Porazinski, None..
M. J. Herold, None..
G. Neely, None..
M. Pajic, None.