| Project Detail |
Unravelling the networks of immune stromal interactions in the tumour microenvironment Few cancer patients benefit from immunotherapy. Even then, tumour evasion mechanisms disrupt treatments, not only in tumour cells, but also in the stromal compartment of the tumour microenvironment (TME), often dismissed as a prospective intervention target. Insight into immune-tumour interactions is therefore critical to develop new treatments. The ERC-funded EPIC project will thoroughly investigate immune and stromal cell interactions in the TME, mapping the roles and pathways of each active cellular element, including multilevel interactions that occur before and after therapeutic intervention. It will then test and validate potential candidates for targeted rational combination therapy in vivo. The results will provide a framework to better understand tumour immunity dynamics, thus leading to novel therapeutic strategies. Immune cells monitor and eliminate cancer cells, and thus keep tumors in check along the lifespan of an organism. However, tumors have evolved various mechanisms to avoid immune surveillance. Therefore, understanding these mechanisms and interfering with them to facilitate immune cell eradication of tumor cells is the focus of many successful immunotherapies. However, the efficacy of immunotherapy is limited to only a small fraction of patients and only certain types of cancers. Therefore, it is crucial to understand the immune-tumor interactions to develop new treatments. Moreover, tumor evasion mechanisms interfere with such treatments, as compensatory programs ensue soon after therapeutic intervention. These compensatory programs are not limited to tumor cells, but also occur in the stromal compartment of the tumor microenvironment (TME), which provides indispensable support to the tumor, and is often overlooked as potential target for intervention. Here we aim to gain a fundamental understanding of all cellular networks within the TME, to elucidate the roles and programs carried out by each cellular element participating in the complex, multilevel interactions that occur before therapeutic intervention and afterward. Toward this goal, we will map the entire spectrum of immune and stromal cell interactions in the TME. We will identify negative- and positive-tumor-regulator dependent programs, primary and compensatory, unique and shared-across pathogenic conditions, and cell-intrinsic and extrinsic programs (Aim 1). Additionally, we aim to identify conserved mouse and human pathways using a parallel mouse and human tumor slice culture system (Aim 2). Based on Aims 1 and 2, we will test and validate new candidates for targeted rational combination therapy in-vivo (Aim 3). Our findings will lay the foundations for a fundamental understanding of tumor immunity dynamics in the TME and create a paradigm shift in immunotherapy |
