December 1, 2001 – Immune checkpoint blockade works by blocking an inhibitory immune signal and reinvigorating exhausted T cells to kill cancer cells. However, only a minority of patients benefit from this treatment and responses can be short-lived. Understanding more about the molecular mechanisms of T cell exhaustion and reinvigoration could enable the design of new strategies to enhance the durability of immune checkpoint blockade therapy and expand its utility for cancer patients.
Alterations to chromatin—the collective term for DNA and its histone protein scaffolding—can stably silence genes and prevent exhausted T cells from being reinvigorated. Ludwig Oxford’s Yang Shi’s laboratory explored the changes in chromatin during T cell exhaustion. They discovered that LSD1, an enzyme that removes methyl groups from histone proteins, is an important regulator of T cell exhaustion in cancer.
Their study, published in Nature Communications, shows that inhibiting LSD1 in mice increases the subset of exhausted T cells that can be reinvigorated by immune checkpoint blockade. 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.