Improving the Clinical Significance of Preclinical Immunotherapy Studies through Incorporating Tumor Microenvironment-like Conditions.

Abstract

Frequently, the results generated when testing novel antitumor immunotherapies <i>in vitro</i> do not correlate with data collected in <i>in vivo</i> models and/or in clinical settings. It is our hypothesis that this discrepancy is caused by the use of <i>in vitro</i> conditions, such as normoxia, a two-dimensional surface, optimal growth media, and lack of cell complexity and heterogeneity. These conditions do not accurately reflect the tumor microenvironment (TME) that the tested immunotherapeutic strategies experience <i>in vivo</i> While there are many variables which can have an impact upon the antitumor efficacy of an immunotherapy, the immunosuppressive TME is one in which several of the conditions commonly found <i>in vivo</i> can be mimicked <i>in vitro</i> These conditions, which include hypoxia, low pH, low glucose, presence of adenosine, cell complexity and heterogeneity, as well as the three-dimensional structure of TME, can all affect immune cell-tumor cell interactions. Here, we discuss the impact that these conditions, either individually or in combination, can have on these interactions. Furthermore, we propose that performing <i>in vitro</i> assays under TME-like conditions improves the clinical relevance of the yielded results. This, in turn, contributes to accelerate the speed, reduce the cost, and increase efficiency of screening novel immunotherapies and eventually the development of prospective clinical trials.