Coupling dead cell recognition to Fcγ receptors augments anticancer immunity.
Castro-Dopico T., Piot C., Buck MD., Gandullo-Sánchez L., Lim KHJ., Gonzales GA., Rosendahl N., Schulz O., Stainier W., Vash B., Maiocco S., Henry CM., Frederico B., Lee S., Zhang AB., Rogers NC., Bordoloi J., Roustan C., Kjaer S., Trikha M., Stauss H., Hazini A., Radford KJ., Tuong ZK., Canton J., Mehta R., Reis E Sousa C.
Type 1 conventional dendritic cells (cDC1s) are key antigen-presenting cells (APCs) for cross-priming of CD8+ T cells against cancer. They can capture and cross-present dead cell antigens via DNGR-1 (CLEC9A), a receptor for F-actin exposed on cell corpses. However, cDC1s are scarce in human and murine tumors, and this restricts anticancer immunity. We show that abundant tumor-associated APCs, including cDC2s and monocyte-derived cells, can be redirected to internalize necrotic debris and cross-present associated antigens by a variety of reagents that bridge F-actin to Fcγ receptors (FcγRs), including an Fc-DNGR-1 fusion protein and an anti-F-actin antibody. In vivo, Fc-DNGR-1 accumulates in necrotic tumor areas and highlights their proximity to intratumoral FcγR+ APCs. In mouse cancer models, F-actin-FcγR bridging enhances tumor control and synergizes with cytotoxic chemotherapy or radiotherapy. Thus, nonspecialized APCs can be harnessed for cross-presentation of necrotic tumor antigens, and F-actin-FcγR bridging constitutes a strategy to potentiate anticancer immunity.