Efficacy evaluation of candidate therapeutics in immuno-oncology by in vitro suppressive bioassays using macrophages or MDSC

The increasing interest in the tumour microenvironment leads to a focus on new bioassays to represent all the players of the cancer immune response. Some of these players like Tumour Associated Macrophages (TAMs) and Myeloid Derived Suppressor Cells (MDSCs) play an important role by downregulating the anti-tumour response. Their regulation mechanisms constitute an important target for new therapeutics. In order to study these mechanisms in a human model, suppressive bioassays mimicking the suppressive action of these cells on T cell activation, were developed. An important player in the tumor microenvironment are macrophages which possess important active and regulatory functions in both innate and adaptive immune responses. Classical activated macrophages, classified as M1-like macrophages, comprise immune effector cells with an acute inflammatory phenotype while the alternatively activated M2-like macrophages have suppressive and healing capacities. TAMs are present at high densities in solid tumors and share many characteristics with M2-like macrophages. In vitro assays using M1- and M2-like macrophages can be a first step to screen the effect of the test molecules on the phenotype and function of macrophages. For example, macrophage precursors display extraordinary plasticity in response to exogenous and endogenous stimuli which can result in a M2- or M1-like status. Using in vitro polarization and functional assays, the potential effect of molecules on M1- and M2-like macrophage generation and polarization can be screened. Next to that, the test molecules' impact on the functionality of macrophages can be evaluated in a suppressive assay. Here, the ability of the molecules to reverse the stimulating versus suppressive effect of the M1- and M2-like macrophages on T cells can be determined by measuring proliferation and cytokine production. MDSCs present a highly suppressive phenotype in the tumour microenvironment. Their role in relation to cancer development and progression has shown to be of great importance. Therefore, the ability of molecules to reverse the suppressive function of the MDSCs can be evaluated in vitro using specific suppressive bioassays. The use of bioassays contributes to a better understanding of the tumour microenvironment. The steps needed to generate an anti-tumour response by the immune system will help to assess the functional potential of new drugs, design clinical trials and ultimately discover relevant biomarkers.