The Geiger lab
T cells are key players in the immune system with the ability to detect and eliminate infected cells and tumors. We study molecular regulations underlying T cell activation and anti-tumor activity. For this, we use a wide range of technologies including mass spectrometry-based proteomics, functional genomics, mouse models and microfluidics-based systems. Our projects aim to provide detailed insights into T cell functionality that can be translated into the clinic to improve anti-cancer immunotherapies.
Quantitative Molecular Analysis of the T cell Response
To explore molecular mechanisms underlying the T cell response, we use quantitative systems approaches including mass spectrometry-based proteomics, RNA-Seq, ATAC-Seq as well as several targeted approaches.
Immune Response to Liver Cancer
We are interested in the immune response to liver cancer. T cells that infiltrate liver tumors are often exhausted and do not work properly. To potentially increase their functionality, we study the underlying regulations by systematically analyzing tumor-infiltrating T cells with high-resolution mass spectrometry and functional assays.
Rapid Identification of T cell Receptors that recognize Tumor Antigens
We develop workflows to efficiently isolate T cells that recognize liver tumor antigens. Tumor-reactive T cells can be grown to large numbers and used for adoptive T cell therapies, a highly personalized form of cancer therapy. In collaboration with the research group of Andrew deMello (ETH Zürich), we use droplet-based microfluidics systems to manipulate and analyze single T cells in a high-throughput format.
Matteo Pecoraro, PhD
Matteo obtained his PhD at the Universitat Autònoma de Barcelona. He then received postdoctoral training in the laboratory of Matthias Mann at the Max Planck Institute in Munich, Germany. He joined the Geiger lab in 2019 as a research specialist is mass-spectrometry based proteomics.
Giulia obtained her bachelor degree at University of Milano Bicocca and completed her Master in Applied Biotechnology at Uppsala University in Sweden. During her training she focused on CAR T cell immunotherapy in Magnus Essand's Lab, where she also worked before joining Geiger's group in March 2021.
Ian completed his bachelor and master degrees at McGill University in Montréal, Canada. He then worked as a research associate in the labs of Judy Sakanari and Alexander Marson at the University of California, San Francisco (UCSF) before joining the Geiger Lab in 2019 as a PhD student.
Lorenzo obtained his bachelor and master degree in Life Sciences and Technologies from the Swiss Federal Institute of Technology in Lausanne (EPFL). He then worked as a junior engineer in the field of microfluidics at IBM Research in Zürich, before joining the Geiger Lab in September 2020.
We use droplet-based microfluidics devices that are developped in the laboratory of Professor deMello.
in Nature, October 2021
The availability of L-arginine in tumours is a key determinant of an efficient anti-tumour T cell response. Consequently, increases of typically low L-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies5. However, currently no means are available to locally increase intratumoural L-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours6, to L-arginine. Colonization of tumours with these bacteria increased intratumoural L-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.
sustaining T cell preparedness
in Nature Immunology, August 2020
In response to pathogenic threats, naive T cells rapidly transition from a quiescent to an activated state, yet the underlying mechanisms are incompletely understood. Using a pulsed SILAC approach, we investigated the dynamics of mRNA translation kinetics and protein turnover in human naive and activated T cells. Our datasets uncovered that transcription factors maintaining T cell quiescence had constitutively high turnover, which facilitated their depletion following activation. Furthermore, naive T cells maintained a surprisingly large number of idling ribosomes as well as 242 repressed mRNA species and a reservoir of glycolytic enzymes. These components were rapidly engaged following stimulation, promoting an immediate translational and glycolytic switch to ramp up the T cell activation program. Our data elucidate new insights into how T cells maintain a prepared state to mount a rapid immune response, and provide a resource of protein turnover, absolute translation kinetics and protein synthesis rates in T cells (https://www.immunomics.ch).
in Cell, October 2016
Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses.
Meet the lab
We welcome all applications from individuals who are passionate about applying new technologies to studying the immune response to tumors. Please contact Roger with your CV and a cover letter.
Currently, we are actively recruiting two positions: Research Associate and a Postdoctoral scholar. See links below for more information.