Coupling dead cell recognition to Fcγ receptors augments anticancer immunity
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Tom Castro Dopico Cecile Piot Michael Buck Lucia Gandullo Sanchez Jonathan Lim Gerone A Gonzales Nikita Rosendahl Oliver Schulz William Stainier Brian Vash Stephanie Maiocco Conor Henry Bruno Frederico Sonia Lee Andy Zhang Neil Rogers Jayanta Bordoloi Chloe Roustan Svend Kjaer Mohit Trikha Hans Stauss Ahmet Hazini Kristen J Radford Zewen Kelvin Tuong Johnathan Canton

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Abstract

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.