Microfluidic Co-Culture Models for Dissecting the Immune Response in in vitro Tumor Microenvironments (original) (raw)

Microfluidics: A new tool for modeling cancer-immune interactions

Trends in cancer, 2016

In recognition of the enormous potential of immunotherapies against cancer, research into the interactions between tumor and immune cells has accelerated, leading to the recent FDA approval of several drugs that reduce cancer progression. Numerous cellular and molecular interactions have been identified by which immune cells can intervene in the metastatic cascade, leading to the development of several in vivo and in vitro model systems that can recapitulate these processes. Among these, microfluidic technologies hold many advantages in terms of their unique ability to capture the essential features of multiple cell type interactions in three-dimensions while allowing tight control of the microenvironment and real-time monitoring. Here, we review current assays and discuss the development of new microfluidic technologies for immunotherapy.

Cross talk between cancer and immune cells: exploring complex dynamics in a microfluidic environment

The reconstitution of a complex microenvironment on microfluidic chips is one of the cornerstones to demonstrate the improved flexibility of these devices with respect to macroscale in vitro approaches. In this work, we realised an on-chip model to investigate the interactions between cancer and immune system. To this end, we exploited mice deficient (Knock Out, KO) for interferon regulatory factor 8 (IRF-8), a transcription factor essential for the induction of competent immune responses, to investigate how IRF-8 gene expression contributes to regulate immune and melanoma cells crosstalk. In vivo, IRF-8 KO mice are highly permissive to B16 melanoma growth due to failure of immune cells to properly exert immunosurveillance. B16 cells and immune cells isolated from the spleen of wild type (WT) and IRF-8 KO mice were co-cultured for one week in a PDMS platform and monitored by fluorescence microscopy and time-lapse recordings. We observed that WT spleen cells migrated through microchannels connecting the culturing chambers towards B16 cells and tightly interacted with tumor cells, forming clusters of activation. In contrast, IRF-8 KO immune cells poorly interacted with melanoma cells. In parallel, B16 cells were more attracted towards microchannels, acquiring a more invasive behaviour in the presence of IRF-8 KO spleen cells, with respect to WT cells. Our results strongly confirm the in vivo observations and highlight the value of on-chip coculture systems as a useful in vitro tool to elucidate the reciprocal interactions between cancer cells and host immune system, with relevant impact in the development of more effective anti-tumor therapeutic strategies.

3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade

Lab on a chip, 2018

Microfluidic culture has the potential to revolutionize cancer diagnosis and therapy. Indeed, several microdevices are being developed specifically for clinical use to test novel cancer therapeutics. To be effective, these platforms need to replicate the continuous interactions that exist between tumor cells and non-tumor cell elements of the tumor microenvironment through direct cell-cell or cell-matrix contact or by the secretion of signaling factors such as cytokines, chemokines and growth factors. Given the challenges of personalized or precision cancer therapy, especially with the advent of novel immunotherapies, a critical need exists for more sophisticated ex vivo diagnostic systems that recapitulate patient-specific tumor biology with the potential to predict response to immune-based therapies in real-time. Here, we present details of a method to screen for the response of patient tumors to immune checkpoint blockade therapy, first reported in Jenkins et al. Cancer Discovery...

Microfluidic models for adoptive cell-mediated cancer immunotherapies

Drug discovery today, 2016

Current adoptive T cell therapies have shown promising results in clinical trials but need further development as an effective cancer treatment. Here, we discuss how 3D microfluidic tumour models mimicking the tumour microenvironment could help in testing T cell immunotherapies by assessing engineered T cells and identifying combinatorial therapy to improve therapeutic efficacy. We propose that 3D microfluidic systems can be used to screen different patient-specific treatments, thereby reducing the burden of in vivo testing and facilitating the rapid translation of successful T cell cancer immunotherapies to the clinic.

Microfluidic devices to enrich and isolate circulating tumor cells

Lab on a Chip, 2015

Detection of circulating tumor cells (CTCs) in blood has been extensively investigated to use them as a biomarker for the diagnosis and prognosis of various cancers. This review provides a comprehensive overview of recent advances in CTC detection achieved through application of microfluidic devices and the challenges that these promising technologies must overcome to be clinically impactful.