A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model

The success of immunotherapeutic approaches strictly depends on the immune cells interaction with cancer cells. While conventional in vitro cell cultures under-represent the complexity and dynamic crosstalk of the tumor microenvironment, animal models do not allow deciphering the anti-tumor activity of the human immune system. Therefore, the development of reliable and predictive preclinical models has become crucial for the screening of immune-therapeutic approaches. We here present an organ-on-chip organ on chips (OOC)-based approach for recapitulating the immune cell Natural Killer (NK) migration under physiological fluid flow, infiltration within a 3D tumor matrix, and activation against neuroblastoma cancer cells in a humanized, fluid-dynamic environment. Circulating NK cells actively initiate a spontaneous extravasation process toward the physically separated tumor niche, retaining their ability to interact with matrix-embedded tumor cells, and to display a cytotoxic effect (tumor cell apoptosis). Since NK cells infiltration and phenotype is correlated with prognosis and response to immunotherapy, their phenotype is also investigated: most importantly, a clear decrease in CD16-positive NK cells within the migrated and infiltrated population is observed. The proposed immune-tumor OOC-based model represents a promising approach for faithfully recapitulating the human pathology and efficiently employing the immunotherapies testing, eventually in a personalized perspective. An immune-organ on chip to recapitulate the tumor-mediated infiltration of circulating immune cells within 3D tumor model.

Automated summary

The success of immunotherapeutic approaches depends on the interaction between immune cells and cancer cells. Conventional cell cultures and animal models cannot fully represent the complexity of the tumor microenvironment and the human immune system. Therefore, it is crucial to develop reliable and predictive preclinical models for screening immunotherapeutic approaches. This study presents an organ-on-chip (OOC)-based approach that can mimic the migration of natural killer (NK) cells, infiltration into a 3D tumor matrix, and activation against neuroblastoma cancer cells in a fluid-dynamic environment. The proposed immune-tumor OOC-based model shows promise in faithfully replicating human pathology and effectively testing immunotherapies, potentially in a personalized perspective.