School of Biological and Health Systems Engineering (SBHSE), Arizona State University, Tempe, AZ, 85287, USA.
School for Engineering of Matter, Transport and Energy (SEMTE), Arizona State University, Tempe, AZ, 85287, USA.
Adv Healthc Mater. 2024 Jun;13(14):e2303658. doi: 10.1002/adhm.202303658. Epub 2024 Feb 25.
Evolving knowledge about the tumor-immune microenvironment (TIME) is driving innovation in designing novel therapies against hard-to-treat breast cancer. Targeting the immune components of TIME has emerged as a promising approach for cancer therapy. While recent immunotherapies aim at restoring antitumor immunity, counteracting tumor escape remains challenging. Hence there is a pressing need to better understand the complex tumor-immune crosstalk within TIME. Considering this imperative, this study aims at investigating the crosstalk between the two abundant immune cell populations within the breast TIME-macrophages and T cells, in driving tumor progression using an organotypic 3D in vitro tumor-on-a-chip (TOC) model. The TOC features distinct yet interconnected organotypic tumor and stromal entities. This triculture platform mimics the complex TIME, embedding the two immune populations in a suitable 3D matrix. Analysis of invasion, morphometric measurements, and flow cytometry results underscores the substantial contribution of macrophages to tumor progression, while the presence of T cells is associated with a deceleration in the migratory behavior of both cancer cells and macrophages. Furthermore, cytokine analyses reveal significant upregulation of leptin and RANTES (regulated on activation, normal T Cell expressed and secreted) in triculture. Overall, this study highlights the complexity of TIME and the critical role of immune cells in cancer progression.
不断发展的肿瘤免疫微环境(TIME)知识正在推动针对难治性乳腺癌的新型治疗方法的创新。针对 TIME 的免疫成分已成为癌症治疗的一种有前途的方法。虽然最近的免疫疗法旨在恢复抗肿瘤免疫,但对抗肿瘤逃逸仍然具有挑战性。因此,迫切需要更好地了解 TIME 内复杂的肿瘤免疫相互作用。有鉴于此,本研究旨在使用器官型 3D 体外肿瘤芯片(TOC)模型研究乳腺 TIME 中两种丰富的免疫细胞群——巨噬细胞和 T 细胞之间的串扰,以推动肿瘤进展。TOC 具有独特但相互关联的器官型肿瘤和基质实体。这个三培养平台模拟了复杂的 TIME,将两种免疫细胞群嵌入到合适的 3D 基质中。入侵分析、形态测量测量和流式细胞术结果表明,巨噬细胞对肿瘤进展有很大的贡献,而 T 细胞的存在与癌细胞和巨噬细胞迁移行为的减缓有关。此外,细胞因子分析显示三培养中瘦素和 RANTES(激活调节正常 T 细胞表达和分泌)的显著上调。总的来说,这项研究强调了 TIME 的复杂性和免疫细胞在癌症进展中的关键作用。