Scientists in Switzerland have made new discoveries which they say improves understanding of exhaustion in white blood cells during the response to cancer.
Tumour-specific CD8 T cells can enter a state of exhaustion in the tumour microenvironment because of sustained stimulation by antigens from the tumour. This causes reduced production of anti-tumour proteins, explains Dr Marcel Trefny of the University of Basel, lead author of the study.
In Nature Communications, the team write: “The pivotal role of tumour-specific CD8 T cells in anti-tumour immunity has fuelled the development of therapeutic strategies that prevent or revert tumour-associated T cell exhaustion.”
They carried out a CRISPR/Cas9 genetic screen of human T cells in the lab to identify genes involved in T cell exhaustion, and identified the gene SNX9 as playing a critical role. Further experiments showed that deleting SNX9 improves T cell function and leads to better anti-tumour action of T cells, in mouse models of cancer.
“We thereby identify a therapeutic strategy to improve T cell-based immunotherapies by limiting excessive stimulatory signals and thereby alleviate T cell exhaustion,” they write.
Dr Trefny said: “The SNX9 gene seems to increase the short-term immune response, which can prove important in situations in which every hour counts to tackle a disease. In the case of our experiment, however, suppressing the SNX9 gene enabled finer adjustment of immune cell activity by reducing excessive stimulation signals.
“The T cells’ activity was therefore conserved over a longer period.”
Co-author Dr Alfred Zippelius added: “The discovery of the role of this gene opens up new approaches for more efficient immunotherapies.”
Trefny MP, Kirchhammer N, Auf der Maur P, Natoli M, Schmid D, Germann M, Fernandez Rodriguez L, Herzig P, Lötscher J, Akrami M, Stinchcombe JC, Stanczak MA, Zingg A, Buchi M, Roux J, Marone R, Don L, Lardinois D, Wiese M, Jeker LT, Bentires-Alj M, Rossy J, Thommen DS, Griffiths GM, Läubli H, Hess C, Zippelius A. (2023) “Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.” Nature Communications, doi: 10.1038/s41467-022-35583-w
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