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

Frequently, the results generated when testing novel antitumor immunotherapies in vitro do not correlate with data collected in in vivo models and/or in clinical settings. It is our hypothesis that this discrepancy is caused by the use of in vitro 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 in vivo 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 in vivo can be mimicked in vitro 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 in vitro 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. ©2020 American Association for Cancer Research.