A team co-led by Ludwig Oxford’s Yang Shi reported in Nature Communications that the epigenetic enzyme LSD1 is an important modulator of T cell exhaustion and that its inhibition could significantly enhance anti-PD-1 immunotherapy. T cells that are unproductively activated by antigen over long periods, as they are in tumors, become lethargic and dysfunctional—a state known as “exhaustion.” A subset of such cells, known as progenitor-exhausted T cells, can be reinvigorated by anti-PD-1 immunotherapy. Yang and his team show in their November paper that LSD1 loss or inhibition in mice significantly expands the progenitor exhausted pool of T cells in multiple mouse models of cancer, serving as a source of more specialized T cells with enhanced anti-tumor activity. They found that LSD1 physically interacts and inhibits TCF1, a regulator of gene expression essential to the progenitor-exhausted T cell identity. Inhibiting LSD1 with small drug-like molecules restores TCF1 function and promotes longer lasting responses to anti-PD-1 immunotherapy. Yang and his colleagues suggest that if biomarkers associated with this mechanism of resistance are identified, eligible patients could receive LSD1 inhibitors in combination with checkpoint blockade immunotherapy. They also suggest the TCF1-LSD1 interaction is a sound target for drug development.
This article appeared in the May 2022 issue of Ludwig Link. Click here to download a copy (PDF, 2MB).