Abstract 2120: In vitro suppressive bioassays using macrophages for the evaluation of immuno-oncology drug

Abstract

Abstract Targeted activation of tumor infiltrating lymphocytes in the tumor microenvironment (TME) with so-called immune checkpoint inhibitors (ICIs) has resulted in the development of revolutionizing therapeutic anti-tumor strategies. A deepening understanding of the TME has followed in the ability to see beyond current immune checkpoint strategies. It becomes clear that players like Tumor Associated Macrophages (TAM) and Myeloid Derived Suppressor Cells (MDSC) play a significant role by downregulating anti-tumor responses. Their presence and roles in the TME open novel possibilities for modulation of the TME. To study these mechanisms, bioassays mimicking the suppressive activity of these cells on lymphocytes were developed. With regulatory functions in both innate and adaptive immune responses and different phenotypic profiles that classically are divided into M1-like and M2-like, macrophages undeniably represent important players in the TME. Where classically activated M1-like macrophages comprise immune effector cells with an inflammatory phenotype, alternatively activated M2-like macrophages display suppressive activities. Correspondingly, a variety of solid tumors are found to be enriched with these M2-like macrophages, suppressing anti-tumor immunity. The diverse roles of macrophage subtypes are still being explored and their phenotypic classification is likely more complex than the classical M1-like and M2-like. However, in vitro assays based on these 2 subtypes can be a first step to screen for the impact of test molecules on the phenotype and function of macrophages and their subsequent effect on lymphocytes. Using in vitro polarization and functional assays, the impact of test molecules on M1-like and M2-like macrophage generation and polarization can be assessed. The impact of test molecules on macrophage functionality can be further evaluated using a macrophage suppressive assay. Here the ability of test molecules to enhance the stimulating effect of M1-like macrophages or to reverse the suppressive effect of M2-like macrophages on lymphocytes can be evaluated by assessing their proliferation and cytokine production. Moreover, the potential stimulatory effect of test compounds on macrophages to perform Antibody-dependent cellular phagocytosis (ADCP) of tumor cells in co-culture assays could be another strategy to review therapeutic potential. Collectively, the development of novel bioassays contributes to a better understanding of the TME and thereby illuminates the steps required to elicit anti-tumor immune responses. It further aids the functional assessment of potential of new drugs, the design of clinical trials and the discovery of relevant biomarkers. Citation Format: Thibaut J. Janss, Simon Lefevre, Martijn Vlaming, Johan Arnold, Ellen Boelen, Sofie Pattijn. In vitro suppressive bioassays using macrophages for the evaluation of immuno-oncology drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2120.