Defining the role of intestinal dendritic cells in anti-colorectal cancer immunity

• Applicant: Dr. Tilman Hölting
• Subject Area: Immunology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546476012

Colorectal cancer is a common cause of morbidity and mortality with increasing incidence in young people. While checkpoint inhibitors have much improved treatment for some patients with remarkable, long-lasting phases of tumor control, most patients’ tumors do not respond. Therefore, further investigation of the immune pathways that suppress anti-tumor immunity in most CRC cases is crucial. Dendritic cells (DCs) play a key role in regulating T cell responses required for clearance of tumor cells and represent a primary target of checkpoint inhibitors. Preliminary data suggest tissue-adaptation of intestinal DCs with enhanced immune-regulatory, tolerance inducing phenotypes imprinted by the intestinal micro-environment. Although intestinal DCs with enhanced tolerogenic properties may help maintain immune tolerance to the gut microbiota and food antigens, it can be hypothesized that intra-tumoral intestinal DCs may also suppress immune responses to neo-antigens upon migration to tumor-draining lymph nodes and that this could be a factor limiting the development of effective anti-tumor immunity to colorectal tumors. By using state-of-the-art single-cell profiling, this project aims to identify rare but critical cell types within tumors and tumor-draining lymph nodes. Additionally, novel genetic models will be used to investigate the crucial molecules that underpin the tolerogenic program of intestinal DCs. The objectives of this project are to determine (i) the role of dendritic cells in anti-tumor immunity in colorectal cancer and (ii) the impact of the microbiota on shaping the fate and function of intestinal dendritic cells. Understanding the tissue and tumor-specific features of CRC-associated DCs and the environmental cues that regulate their fate and function is crucial for identifying pathways that can be selectively modulated to promote effective anti-tumor immune responses.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Chrysothemis Brown, Ph.D.