Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

Abstract

Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.

Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models

“…It can be observed from Table 2 that several studies concerning PDT-induced immune responses were performed on in vivo tumor models. According to Poggi et al [ 11 ], innate cells such as NK cells do not exhibit similar phenotypical and functional features in xenograft models and humans. Thus, more studies are needed in 3D tumor models to better resemble the in vivo human tumor environment before proceeding to costly and time-consuming animal studies.…”

“…Although these animal studies improve the success rates of anticancer agents in clinical trials, murine models poorly reflect the physiological conditions in humans as they inherently contain non-human host cells [ 10 , 104 ]. Furthermore, besides the high cost and ethical complexities, the rate of tumor growth in immunocompromised xenograft models is faster than in natural human tumors and thereby responding better to anticancer drugs [ 10 , 11 ].…”

“…2 of 24 [10,11]. In this context, three-dimensional (3D) tumor spheroids have been proposed as excellent culture models to reduce the number of animals used and possibly replace cumbersome and expensive animal models.…”

“…As traditional two-dimensional (2D) cell cultures lack cell–cell interactions and the essential tumor microenvironment responsible for tumor signaling and drug response, significant discrepancies have been reported when comparing the outcomes to in vivo experiments [ 10 ]. Thus, in vivo experiments have been extensively conducted, using immune-suppressed animal models that may not fully reflect what happens in humans [ 11 ]. However, animal-based models harbor tumors that have been artificially generated in a short period.…”

“…However, animal-based models harbor tumors that have been artificially generated in a short period. Moreover, immune cell subsets and receptor–ligand pairs, which are imperative for tumor cell recognition and antitumor immune responses, are often different from their human counterparts [ 10 , 11 ]. In this context, three-dimensional (3D) tumor spheroids have been proposed as excellent culture models to reduce the number of animals used and possibly replace cumbersome and expensive animal models.…”