How the activity of specific genes, but also the fraction of our genome that does not contain genes (the "non-coding" genome), regulates T cell exhaustion is incompletely understood.
Researchers from the LIT and the DKFZ now shed light into this process by deep analysis of thousands of functional as well as exhausted T cells that they derived from human cancer patients. They focused their attention on the activity of the non-coding genome that makes up to 99% of our DNA, and how it is regulating and "fine-tuning" the activity of the genes that determine the anti-tumor-activity of our T cells.
By using modern single-cell sequencing methods, the scientists 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 head and neck squamous cell carcinoma. These observations show, that despite the heterogeneous nature of tumor-infiltrating T cells, a common molecular process irrespective of the specific cancer type can drive T cell exhaustion.
To look for ways to manipulate genes important for the anti-cancer activity of T cells, the researchers employed altered CRISPR "gene-scissors" that were not used to cut DNA, but activate or repress non-coding elements in the genome to impact the activity of nearby genes. With this method, the activity of genes such as the unfavorable inhibitory immune checkpoint PD1, or the beneficial gene TCF7 could be changed.
"These findings not only help us to better understand how T cells regulate the activity of their genes in general. It also enables us to fine-tune genes in T cells that are used in anti-cancer therapy such as CAR T cells, and make this treatment more efficient in the future." says Christian Schmidl, who coordinated the study.
Study: "Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells". Published on the 18th of January 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
*) equal contribution