The development of immunotherapies against leukaemia could be improved if T cells are activated moderately, not excessively, results from a German study have suggested.
In a mouse model, scientists from the German Cancer Research Centre, Heidelberg, found that blocking a cytokine that slows down the immune system renders the T cells exhausted, meaning it could not fight the disease.
The most successful and widely used immunotherapies target immune checkpoint molecules, which act like natural brakes on the immune system. Checkpoint inhibitors release these brakes so the T cells of the immune system recognise and attack tumours. However, available checkpoint inhibitors are far from effective against all types of cancer.
Dr Martina Seiffert and her team at the German Cancer Research Centre (Deutsches Krebsforschungszentrum) searched for other molecules that act as immune brakes and that are suitable as targets for therapies against chronic lymphocytic leukaemia (CLL). The team focused particularly on the immune messenger interleukin 10 (IL-10), of which CLL patients have higher concentrations than healthy individuals.
Because IL-10 suppresses the immune system, the researchers hypothesised that inhibiting IL-10 could help the T cells of CLL patients attack and destroy the leukaemia cells.
But when IL-10 blockers were tested in mice, the disease took a more severe course in mice that had been given IL-10 inhibitors compared to untreated animals – the opposite of what was expected.
Writing in the journal Immunity, they say they found that while inhibiting IL-10 activates T cells, it does so to an extreme degree. This means the T cells become exhausted and eventually lose their ability to fight the tumour.
“In a way, this is a lesson in ‘moderation’ of the immune system,” said Dr Seiffert. “Moderation signals are critical to protect immune cells from going completely haywire.”
The researchers believe their findings could be significant in the development of new cancer immunotherapies. They say if new immunotherapies were developed using ‘moderation’, the success rate and duration of response to cancer immunotherapies could be significantly improved.
Hanna BS, Llaó-Cid L, Iskar M, Roessner PM, Klett LC, Wong JKL, Paul Y, Ioannou N, Öztürk S, Mack N, Kalter V, Colomer D, Campo E, Bloehdorn J, Stilgenbauer S, Dietrich S, Schmidt M, Gabriel R, Rippe K, Feuerer M, Ramsay AG, Lichter P, Zapatka M, Seiffert M. (2021) “Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity.” Immunity, doi: 10.1016/j.immuni.2021.11.004
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