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Professor Yang Shi’s laboratory uncovers an important role for the chromatin regulator LSD1 in T cell exhaustion and demonstrates that LSD1 inhibition in mice increases the durability of responses to immune checkpoint blockade therapy.

Immune checkpoint blockade therapy is a type of cancer treatment that has achieved great success in some patients. It works by blocking an inhibitory immune signal and reinvigorating exhausted T cells to kill the cancer cells. However, only a minority of patients benefit from this treatment and responses can be short-lived. Understanding more about the molecular mechanisms responsible for T cell exhaustion and the ability of T cells to be reinvigorated may enable the design of new strategies to enhance the durability of immune checkpoint blockade therapy to benefit more patients.

Alterations to chromatin – the structure formed by DNA and histone proteins – have the potential to stably silence genes and prevent exhausted T cells from being reinvigorated. Ludwig Oxford’s Professor Yang Shi’s laboratory studied the changes in chromatin during T cell exhaustion. They uncovered that LSD1, an enzyme that removes methyl groups from histone proteins, is an important regulator of T cell exhaustion in cancer.

Their research, published in Nature Communications, shows that inhibiting LSD1 in mice increases the subset of exhausted T cells that are able to be reinvigorated by immune checkpoint blockade treatment. This led to an increase in activated T cells with cancer-killing function and a longer-lasting response to treatment.

This study provides important new insights into the epigenetic mechanisms regulating T cell exhaustion and suggests that the combination of LSD1 inhibition with immune checkpoint blockade therapy should be investigated further to enhance cancer treatment.


Image credit: NIAID, CC BY 2.0 via Wikimedia Commons

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