RESUMEN
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.
Asunto(s)
Neoplasias de la Mama , Macrófagos , Linfocitos T , Microambiente Tumoral , Microambiente Tumoral/inmunología , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Femenino , Linfocitos T/inmunología , Linfocitos T/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Dispositivos Laboratorio en un Chip , Quimiocina CCL5/metabolismo , Comunicación Celular , Leptina/metabolismoRESUMEN
Cancer thrives in a complex environment where interactions between cellular and acellular components, surrounding the tumor, play a crucial role in disease development and progression. Despite significant progress in cancer research, the mechanism driving tumor growth and therapeutic outcomes remains elusive. Two-dimensional (2D) cell culture assays and in vivo animal models are commonly used in cancer research and therapeutic testing. However, these models suffer from numerous shortcomings including lack of key features of the tumor microenvironment (TME) & cellular composition, cost, and ethical clearance. To that end, there is an increased interest in incorporating and elucidating the influence of TME on cancer progression. Advancements in 3D-engineered ex vivo models, leveraging biomaterials and microengineering technologies, have provided an unprecedented ability to reconstruct native-like bioengineered cancer models to study the heterotypic interactions of TME with a spatiotemporal organization. These bioengineered cancer models have shown excellent capabilities to bridge the gap between oversimplified 2D systems and animal models. In this review article, we primarily provide an overview of the immune and stromal cellular components of the TME and then discuss the latest state-of-the-art 3D-engineered ex vivo platforms aiming to recapitulate the complex TME features. The engineered TME model, discussed herein, are categorized into three main sections according to the cellular interactions within TME: (i) Tumor-Stromal interactions, (ii) Tumor-Immune interactions, and (iii) Complex TME interactions. Finally, we will conclude the article with a perspective on how these models can be instrumental for cancer translational studies and therapeutic testing.