CAncer REsistance to T cell mediated immunotherapy – Dissection of the intercellular CONNECTivity mechanisms to overcome therapeutic resistance (CARE CONNECT)

• Applicant: Dr. Eliana Stanganello
• Subject Area: Hematology, Oncology ; Immunology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558744931

Cancer research have made impressive progress in the last decades. Despite this positive trend, cancer cells have resistance mechanisms in place that often limit complete remission. Intercellular communication is fundamental for homeostasis and has gained increasing attention for its role in cancer development and therapy resistance. Tunneling nanotubes (TNTs) were first described in 2004, acting as molecular highways between cells and enabling direct communication and exchange of cytoplasmic content, including proteins, nucleic acids, and whole organelles. These cellular structures are built up by thin, elongated actin-rich membrane channels. TNTs were shown to be functionally active in the physiological as well as the pathological context. Their presence was shown in human cancer samples, and a contribution of TNTs to tumor progression, invasion, and therapy resistance was reported in several publications. Recently, a unidirectional passage of mitochondria via TNTs between T-cells and cancer cells was observed. In this project, we want to investigate whether TNTs are involved in immunotherapy resistance and can be used as a target for therapeutic intervention. So far, we were able to visualize and quantify TNTs in MC-38 and CT-26 cells. We observed that in MC-38, TNTs are formed majorly by migratory cellular dislodgment. Furthermore, we showed the presence of Cx43 at the cellular anchor points of TNTs, which allows further testing as a possible target structure for TNT inhibition. Finally, we could visualize the localization of PD-L1 on TNTs and collected the first evidence of TNT-mediated PD-L1 transfer between IFN-gamma stimulated and unstimulated MC-38 cells. The aim of this project is to further characterize these structures and their role in the resistance to immunotherapy.

• DFG Programme: Research Grants