Unraveling and counteracting immunoinhibitory signals of the tumor microenvironment for improved cancer immunotherapy - Project summary/Abstract Macrophages are considered a double-edged sword for tumor cells due to their plasticity in response to different environments. M1-like macrophages (M1) promote immune responses and inhibit tumor growth, while M2-like macrophages (M2) contribute to tumor progression by promoting angiogenesis and suppressing T cell responses. Tumor-associated macrophages (TAMs) predominantly consist of M2 macrophages, creating an immunosuppressive tumor microenvironment (TME). However, the mechanisms regulating macrophage polarization within tumors remain poorly understood. Tumor endothelial marker 8 (TEM8) has emerged as a key biomarker expressed on immunosuppressive cancer-associated fibroblasts (CAFs). Disruption of the Tem8 gene or blocking TEM8 protein has been shown to critically impede tumor growth in mouse models. My preliminary data demonstrate a striking increase in the M1 population within Tem8 knockout (KO) mice compared to wildtype (WT) mice. Notably, through an unbiased high-throughput CRISPR/Cas9 activation library screening, I recently identified TEM8 as a cell surface ligand for a macrophage receptor known as TEM8R, which plays a crucial role in regulating macrophage polarization. Moreover, TEM8 induces degradation of TEM8R through trans-endocytosis. Intriguingly, in vivo studies have demonstrated that monoclonal antibodies (mAbs) targeting TEM8, which effectively block the TEM8-TEM8R interaction, can inhibit tumor growth. Building upon these findings, my hypothesis is that TEM8 facilitates tumor growth by modulating macrophage differentiation in the TME through its interaction with TEM8R. To address this hypothesis, I will first elucidate the role of TEM8R in macrophage polarization within the TME by using the Tem8r KO mouse model I recently created. Subsequently, I will investigate the impact of the TEM8-TEM8R interaction on macrophage polarization and tumor growth using mAbs that specifically block this interaction, as well as a Tem8 mutant mouse model that is defective in this interaction. Furthermore, I will investigate the underlying mechanisms by which TEM8R regulates macrophage polarization and identify the factors governing TEM8R expression during macrophage differentiation. Additionally, I will explore the potential of anti-TEM8R mAbs and small molecule drugs that can disrupt the TEM8-TEM8R interaction as innovative approaches for cancer treatment and chemoprevention. Through unraveling the mechanisms by which TEM8, present on tumor-associated stromal cells, regulates TAM dynamics, these studies have the potential to advance our understanding of immunosuppression in solid tumors and facilitate the development of innovative and effective therapeutic strategies for cancer treatment and prevention.
