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 grownin 2 dimensions (2D), as well as on animal models mainly based on the use of rodents such as miceand rats. However, in vitro 2D conventional cell cultures fail to accurately predict the drug responsesin humans, as they do not properly resemble the spatial complexity of the human tissuemicroenvironment; on the other side, research on living animals did not completely meet thepublic agreement, pointing out ethical questions which have been addressed and regulated by theEuropean Community. In addition to the ethical issues, the heterogeneity of housing conditions, ofmicrobiota and chow compositions and the inability to reproduce the complex interplay betweentumor cells and human microenvironment represent additional weaknesses of the most utilized invivo models (1). Therefore, the progressive switch to 3D experimental material is accompanied byseveral advantages converging in a better reproducibility of the results among different labs.Current 3D cultures are based on the establishment of different models including tumororganoids. These are derived from epithelial cells of many organs and can be ideally establishedfrom each patient, with the possibility to comparatively analyze tumor and normal tissue from thesame individual, in the context of personalized medicine (2). As they originate from stem cells, theyhave the capacity to self-organize and self-renew (2). There are also several possibilities to mimic thetumor microenvironment (TME) in 3D structures. This TME contains various organic andinorganic molecules belonging to extracellular matrix and several non-cancerous cell types thatnevertheless create a strongly immunosuppressive environment rendering the cancer resistant tomany treatment options (3). The 3D models likewise allow to evaluate treatment efficiency for theindividual patient, for example the response to checkpoint inhibitors, correlated with clinicalresponses (4). Experimental treatments and therapeutic combinations can be tested in 3D tumorspheroid microarrays bringing together NK92-CD16 cells and tumor cell lines with anti-tumorantibodies 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 ofvascularization in the organoids, or the organ-organ cross-talk, that might be circumvented by theuse of organs-on-chip technologies (6).