"Current immunotherapeutic strategies to combat cancer are hampered by the ability of tumors to escape immunity necessitating new mechanistic insights into underlying molecular and cellular processes. Through orchestrating complex cellular moves and determining the positioning of immune cells, chemokines govern both productive immune responses and their silencing. Chemokines signal through classical G-protein coupled receptors (GPCRs) but also bind atypical receptors (ACRs). ACRs modulate chemokine availability and create functional chemokine patterns by either degrading or transporting them. Besides their essential role in tumor immunity, GPCRs can be expressed by the tumor cells themselves and contribute to the formation of metastases, a major cause of death in cancer. Importantly, ACRs are also expressed in tumors but their role in tumor-host interactions is not clear.
The aim of this project is to take a comprehensive look at the contribution to tumor-host interactions of a paradigmatic chemokine axis with pleiotropic involvement in induction and suppression of immunity and driving tumor metastasis. We will investigate the roles of CCL19 and CCL21, their GPCR, CCR7, and ACR, CCRL1, in regulating tumor progression and orchestrating anti-tumor immunity and its suppression, including in the setting of experimental tumor immunotherapy. The proposed work will entail studies of transplanted murine tumors with hosts and tumors having modified expression levels of chemokines, their GPCR and ACR as well as using models with disrupted function of specific immune cells. The host provides state of the art facilities and profound immunological expertise, whereas the applicant brings complementary competence in molecular biology and cancer and will be able to synergize in order to reach the research objectives. This work should lead to a better understanding of chemokine-driven tumor-host homeostasis and suggest novel ways to treat cancer and promote anti-tumor immunity."
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