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Even T cells get tired

  • Date Published

    January 19, 2023

T cells, working within our immune system, can potentially infiltrate tumors and kill cancer cells. But they often get worn out or ‘exhausted’ which puts the brakes on the anti-cancer immune reaction.

Scientists do not yet fully understand how specific genes act to regulate T-cell exhaustion. Nor is the role played by the ‘non-coding’ genome—the fraction of our genome that does not contain genes—completely understood.

However, researchers from the Leibniz Institute of Immunotherapy and the German Cancer Research Center (DKFZ) are now shining a spotlight on this process through their detailed analysis of thousands of both functional and exhausted T cells derived from human cancer patients. They have focused their attention on the role of the non-coding genome that makes up 99% of our DNA, and specifically how it is regulating and ‘fine-tuning’ the activity of the genes that determine how our T cells deal with tumors.

By using modern single-cell sequencing methods, the scientists have discovered common sets of non-coding DNA elements in exhausted T cells that were shared between different cancer types such as liver cancer, renal cancer, or squamous cell carcinoma of the head and neck. These observations show, that despite the heterogeneous nature of tumor-infiltrating T cells, a common molecular process can drive T-cell exhaustion irrespective of the specific cancer type.

In their search for ways to manipulate the genes influencing the anti-cancer activity of T cells, the researchers employed altered CRISPR ‘gene-scissors.’ These were not used to cut DNA, but to activate or repress non-coding elements in the genome in order to impact the activity of nearby genes. With this method, the activity of genes such as the harmful inhibitory immune checkpoint PD1 or the beneficial gene TCF7 could be changed.

Graphical abstract of the study

Study: “Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.” Published January 18 2023 in the journal Molecular Cell  doi.org/10.1016/j.molcel.2022.12.029

Authors: Dania Riegel*, Elena Romero-Fernández*, Malte Simon*, Akinbami Raphael Adenugba, Katrin Singer, Roman Mayr, Florian Weber, Mark Kleemann, Charles D. Imbusch, Marina Kreutz, Benedikt Brors, Ines Ugele, Jens M. Werner, Peter J. Siska, Christian Schmidl

*joint contributors

These findings not only help us to better understand how genes regulate T-cell response to tumors. They also enable us to fine-tune the activity of genes in T cells. This will make treatment more efficient in the future.
Dr. Christian Schmidl
Head of Research Group Epigenetic Immuno-oncology