Dissecting the epigenetic regulation of chemokine and chemokine receptor expression in dendritic cells and CD8+ T cells in the tumor microenvironment

• Applicant: Paulina Cruz de Casas, Ph.D.
• Subject Area: Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554690704

Chemokines (CKs) are chemotactic cytokines that form tissue microenvironments to modulate immune cell migration and localization within tissues, facilitating cell-to-cell interactions by forming gradients that position these cells in shared niches to increase the likelihood of their encounters. For example, dendritic cells (DCs) are professional antigen presenting cells that coordinate CD8+ T cell activation and differentiation into cytotoxic effector lymphocytes (CTLs). CK-mediated DC-CD8+ T cell interactions are essential for anti-tumor immunity, since the effector function of CTLs supports the clearance of neoantigen-expressing cancer cells. The mechanisms regulating DC-CD8+ T cell interactions in the tumor microenvironment (TME) have not been fully depicted. However, recent studies have shown that intratumoral DCs support CTL proliferation and maintenance through CK-mediated interactions (Di Pilato et al. 2021; Meiser et al. 2023). Due to the modulatory role of CKs in anti-tumoral immunity tumor cells manipulate the CK network to favor their survival and metastasis. Importantly, how CK-related gene expression is epigenetically regulated is not well understood. A detailed characterization of the CK-related mechanisms orchestrating DC-CD8+ T cell interactions in the TME would be a useful tool to improve therapeutic approaches and disease outcome. In this project, we are interested in characterizing the epigenetic regulation of the CK network in the TME, leading to the establishment of "immune niches" that shape the function of CTLs and disease outcome. We will use preclinical mouse models of melanoma tumors implanted into mice to which we will transfer tumor-specific CD8+ T cells. CD8+ T cells and Zbtb46GFP-expressing DCs will be sorted from tumors and draining lymph nodes, and analyzed by single nuclei Multiome Sequencing to predict the promoter, enhancer and silencer regions regulating CK-related gene expression. The predicted regions will then be used to identify the transcription factors (TFs) and mechanisms involved in CK gene expression. Finally, we will disrupt the identified regions and TFs through in vivo CRISPR screenings in CD8+ T cells to test the functional impact of CK network regulation in CTL-dependent anti-tumor immunity. Our results will shed light on the to-date poorly characterized CK-related gene scenery in the TME and ist yet unknown epigenetic landscape coordinating the outcome of the anti-tumoral immune response.

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