Project Details
Projekt
Understanding the role of the intestinal microenvironment leading to checkpoint inhibitor-induced colitis
Applicant
Elisabeth Orgler-Gasche
Subject Area
Gastroenterology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564447067
Checkpoint inhibitor (CPI) therapy has transformed cancer treatment by targeting immune checkpoints such as CTLA-4 and PD-1/PD-L1, allowing the immune system to attack cancer cells. While this approach has shown remarkable efficacy in some cancer types, it frequently causes immune-related adverse events (irAEs). Among these, CPI-induced colitis—a severe gastrointestinal inflammation—affects up to 20% of patients. This underscores the critical role of CTLA-4 and PD-1/PD-L1 in maintaining intestinal immune homeostasis. The efficacy of CPI therapy and the incidence of irAEs are strongly influenced by an individual's intestinal microbiota, highlighting the intricate interplay between immune cells and microbial populations. Understanding this relationship is crucial to addressing the dual challenges of optimizing CPI efficacy while minimizing irAEs. The primary aim of this study is to investigate the regulation of the intestinal immune microenvironment and the pathways driving the CPI colitis. Although the precise pathomechanisms of CPI colitis remain unclear, evidence suggests that checkpoint blockade induces T cell dysregulation in some patients. Preliminary data indicate a pivotal role for tissue-resident memory T cells (Trms), which act as localized first responders within the mucosa. We hypothesize that the inhibitory receptors CTLA-4 and PD-1 are essential for restraining Trms and that their blockade triggers a massive clonal expansion of Trms into cytotoxic T cells, a key step in the development of CPI colitis. Additionally, we propose that treatment with TNFα antibodies facilitates the reversion of cytotoxic T cells to a Trm state while preserving anti-tumor immunity. We further hypothesize that the intestinal microbiota interacts with Trms to induce a pro-inflammatory state, priming Trms for expansion upon CPI exposure. To test these hypotheses, we will analyze longitudinal changes in the immune microenvironment during distinct stages of CPI colitis (pre-development, symptom onset, and treatment) using colon biopsies from melanoma patients. These samples will undergo in-depth single-cell analysis, leveraging data from three separately funded clinical trials of CPI colitis, including a randomized trial comparing TNFα blockade to corticosteroids. To explore the role of the intestinal microbiota, we will analyze fecal samples from patients using 16S rRNA sequencing. Bacterial composition profiles will be correlated with CPI colitis status and immune cell dynamics. This project provides a unique opportunity to advance our understanding of gastrointestinal immune regulation. As immunotherapy continues to revolutionize cancer treatment, addressing the challenges posed by irAEs is essential. By elucidating the mechanisms of CPI-induced colitis, this research aims to improve the safety and effectiveness of CPI therapies, ultimately broadening their clinical utility.
DFG Programme
WBP Fellowship
International Connection
USA
