Crosspresentation of dead cell-associated antigens in immunity to cancer

Cancer immune control relies on cytotoxic T cells that are primed against tumour antigens by crosspresenting type 1 conventional dendritic cells (cDC1s). We have found that the cDC1 receptor, DNGR-1, promotes crosspresentation of dead cell-associated antigens through a novel cell biological mechanism that involves signalling for phagosomal rupture. We propose to screen for further components of the DNGR-1–phagosomal rupture pathway with a view to harnessing them in anti-cancer immunity. Notably, DNGR-1 detects dead cells by binding to F-actin exposed by cell corpses, an activity opposed by secreted gelsolin (sGSN) circulating in plasma or produced by cancer cells. We will examine how the interplay between DNGR-1 and sGSN regulates anti-tumour immunity, including testing the hypothesis that DNGR-1-mediated crosspresentation selects tumour neoantigens associated with the actin cytoskeleton. Finally, as cDC1 are rare in tumours, we will assess the benefit of broadening DNGR-1 expression to other myeloid cells, either genetically or chemically. The latter will involve arming Fcγ receptors, which may also signal for phagosomal rupture, with the DNGR-1 extracellular domain. Altogether, the proposed work will reveal fundamental mechanisms by which the antigenicity of dead cells is translated into anti-tumour responses and suggest avenues to exploit these mechanisms for cancer therapy.