Role of CX3CR1 for the organization of monocyte/macrophage and transitory CTL interactions in the tumor microenvironment

• Applicant: Dr. Julia K. Lill
• Subject Area: Immunology ; Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515639712

In addition to macrophages (MPs) and their circulating monocyte progenitors (MOs), the chemokine receptor CX3CR1 is highly expressed on the transitory effector subset of cytotoxic T cells (CTLs), which have previously been described to be critical for immunological control or chronic viral infection and malignant tumors. However, the function of CX3CR1 on this highly proliferative effector T cell state in the anti-tumor immune response remains unknown. In preliminary studies in mouse cancer models, we observed expression of the CX3CR1 ligand, CX3CL1, on non-hematopoietic cells of the TME, such as fibroblasts, endothelial cells, and cancer cells. Considering that MOs/MPs and transitory CTLs share expression of CX3CR1 and that both are enriched in the tumor microenvironment (TME), this project will test the hypothesis that regional expression of CX3CL1 in the TME results in the formation of discrete tissue niches to which both cell types are recruited. The resulting spatial co-localization in these CX3CL1-niches may facilitate physical interactions and bi-directional crosstalk between CTLs and MOs/MPs. Depending on the immunological context, this crosstalk can be either pro-tumorigenic by enabling CTL suppression by MPs or anti-tumorigenic by enabling tumoricidal MO/MP reprogramming by CTL. Identifying such potential CX3CL1 niches and understanding how they potentially organize CTL – MO/MP crosstalk to affect local CTL and MP anti-tumor activity will not only shed further light on the complex regulatory immune cell networks in the TME but may also inform new strategies to therapeutically improve spontaneous and therapeutically induced immune responses in cancer patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Thorsten Roman Mempel, Ph.D.