Editorial: Recent 3D Tumor Models for Testing Immune-Mediated Therapies

For a long time, cancer research was based on the culture of cell lines and primary tumor cells grown in 2 dimensions (2D), as well as on animal models mainly based on the use of rodents such as mice and rats. However, in vitro 2D conventional cell cultures fail to accurately predict the drug responses in humans, as they do not properly resemble the spatial complexity of the human tissue microenvironment; on the other side, research on living animals did not completely meet the public agreement, pointing out ethical questions which have been addressed and regulated by the European Community. In addition to the ethical issues, the heterogeneity of housing conditions, of microbiota and chow compositions and the inability to reproduce the complex interplay between tumor cells and human microenvironment represent additional weaknesses of the most utilized in vivo models (1). Therefore, the progressive switch to 3D experimental material is accompanied by several advantages converging in a better reproducibility of the results among different labs. Current 3D cultures are based on the establishment of different models including tumor organoids. These are derived from epithelial cells of many organs and can be ideally established from each patient, with the possibility to comparatively analyze tumor and normal tissue from the same individual, in the context of personalized medicine (2). As they originate from stem cells, they have the capacity to self-organize and self-renew (2). There are also several possibilities to mimic the tumor microenvironment (TME) in 3D structures. This TME contains various organic and inorganic molecules belonging to extracellular matrix and several non-cancerous cell types that nevertheless create a strongly immunosuppressive environment rendering the cancer resistant to many treatment options (3). The 3D models likewise allow to evaluate treatment efficiency for the individual patient, for example the response to checkpoint inhibitors, correlated with clinical responses (4). Experimental treatments and therapeutic combinations can be tested in 3D tumor spheroid microarrays bringing together NK92-CD16 cells and tumor cell lines with anti-tumor antibodies triggering antibody-dependent cellular cytotoxicity by the natural killer (NK) cell line (5). However, the current 3D models still have some unmet challenges, such as the absence of vascularization in the organoids, or the organ-organ cross-talk, that might be circumvented by the use of organs-on-chip technologies (6).