Roger Geiger Group
Systems and engineering approaches to cancer immunotherapy
Our laboratory investigates how T cells recognize and eliminate tumors, why these responses fail, and how they can be improved therapeutically. We combine systems immunology with functional genomics, single-cell technologies, quantitative proteomics, microfluidics and synthetic biology to translate fundamental mechanisms into new therapeutic strategies.
Our initial work focused on immunometabolism. By integrating proteomic and metabolomic measurements, we identified intracellular L-arginine as an important determinant of T-cell survival and antitumor activity. We subsequently engineered a probiotic Escherichia coli strain that colonizes tumors and converts locally available ammonia into L-arginine. Combined with PD-L1 blockade, these bacteria increased T-cell infiltration and promoted tumor clearance. We are now developing engineered bacteria that deliver combinations of metabolic and immune-modulating payloads directly within tumors.
A major current focus is the systematic identification of genes that regulate interactions between cytotoxic T cells and cancer cells. We use complementary CRISPR screening approaches in primary human T cells and different cancer models, including droplet-based single-cell screening. These studies identify pathways that control T-cell killing, persistence and differentiation, as well as tumor-intrinsic mechanisms of immune resistance. Our goal is to discover targets that can improve cellular immunotherapies or support effective combination treatments.
We also aim to accelerate the discovery of tumor-reactive T-cell receptors. We are developing high-throughput experimental platforms to generate large, functionally validated datasets of TCR–peptide–MHC interactions and non-interactions. We use these data to train models that predict antigen recognition and potentially dangerous cross-reactivity. Ultimately, we aim to connect tumor sequencing to faster, safer and more affordable personalized TCR-T therapies.
Finally, we are developing human tumor-on-a-chip models to study immune responses in a physiologically relevant environment. Tumor organoids are combined with dendritic cells, T cells and additional stromal or vascular components to reconstruct key steps of the cancer-immunity cycle. These systems allow us to investigate why immune responses fail in different tumor environments and to test whether genetic or pharmacological interventions can restore effective antitumor immunity.
Future Projects and Goals
Our future work will focus on developing experimental and computational tools for immunoengineering and applying them to understand T-cell responses in cancer and autoimmune disease. We will further improve functional genetic screens, TCR–peptide–MHC mapping, human tumor-on-a-chip models and engineered bacterial delivery systems. These approaches will help identify mechanisms that limit antitumor immunity and contribute to the development of new cancer immunotherapies. In parallel, we plan to investigate antigen-specific T-cell responses in autoimmune diseases, identify the pathogenic T-cell clones and antigens involved, and explore strategies to selectively eliminate or modulate disease-causing clones while preserving protective immunity.
Methodological and Technical Expertise
- Primary human T-cell engineering: CRISPR knockout/activation, CAR and TCR expression, expansion and functional characterization.
- Droplet single-cell microfluidics: High-throughput encapsulation, cytotoxicity assays, phenotype-based sorting and perturbation recovery.
- Functional genomics and automated screening: Pooled and arrayed CRISPR screens, robotic cell-based assays and next-generation sequencing readouts.
- Quantitative proteomics and systems biology: Mass-spectrometry-based proteomics, protein-turnover analysis, metabolomics and integrative data analysis.
- Synthetic biology and engineered bacteria: Tumor-colonizing bacterial strains, genetic circuits and local delivery of metabolic or immune-modulating payloads.