Deciphering epigenetically imprinted functional adaptations of tissue-resident memory T cells to guide improved immunotherapy of solid tumors

• Applicant: Dr. Thomas Müller
• Subject Area: Immunology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496946670

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, despite achieving remarkable initial responses, long-term remissions are observed only in a fraction of patients, raising questions about the underlying cellular and molecular mechanisms. It is well known that tissues in general and particularly the tumor microenvironment do provide distinct molecular cues that can irreversibly induce permanent T cell-intrinsic immunosuppressive mechanisms. Tissue-resident memory T cells (TRM) reside in and are functionally adapted to such environments. TRM perform tissue immune surveillance but recent reports also highlight their role in the combat against tumors. To date, however, relatively little is known about TRM due to their difficult probing accessibility.Here, I want to make use of a Europe-wide unique human organ donor cohort (IHOPE) to investigate T cell-intrinsic mechanisms of adaptation to tissue and tumor microenvironment. This project also aims at clinical translation by investigating the role of TRMs at the tumor site and particularly in the context of ICB. To interrogate the molecular basis of TRM functional adaptations, I will isolate effector memory T cells (which includes TRM) from various tissues, tumors, and blood and perform cutting-edge technologies, including multi-parameter flow cytometry, single-cell multiomic epigenetic and transcriptional profiling in combination with TCR sequencing. This comprehensive T cell landscape will inform about TRM differentiation stages and subsets specifically adapted to certain tissue or tumor sites. To mechanistically validate such phenotypes, I will use novel in vitro organoid systems that I will also use to study the effect of ICB on different TRM subsets. Ultimately, I will discover the potential of targeted CRISPR/Cas9-mediated genetic fine tuning of epigenetic regulators as a new strategy to improve immunotherapy of solid tumors.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Marcus Buggert