Novel non-immunogenic trained immunity inducing small molecule with improved anti-tumor properties

Abstract Trained immunity refers to the non-specific innate immune memory response triggered by the epigenetic and metabolic rewiring of innate immune cells. A strengthened innate immune system significantly improves disease resistance. However, very few trained immunity-inducing molecules have been identified. Almost all molecules for training are primarily immunogenic and then subsequently induce training. Non-immunogenic molecules that induce training could be employed in therapies without the concern of adverse inflammatory reactions. We identified a small molecule, A1155463, that modulates cellular metabolism to induce trained immunity in macrophages in-vitro . We show that nanomolar concentrations of these compounds uniquely alter only cellular metabolism without leading to apoptosis. We further observed that these compounds could induce training in an in-vivo model in mice. A1155463 training improved anti-tumor resistance to B16.F10 melanoma cells. The effect was enhanced upon combination with checkpoint therapy. In summary, we report the discovery of a novel trained immunity-inducing small molecule with enhanced anti-tumor properties.