Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy
Ali Ghasemi, Amaia Martínez-Usatorre, Luqing Li, Mehdi Hicham, Alan Guichard, Rachel Marcone, Nadine Fournier, Bruno Torchia, Darel Martinez Bedoya, Suzel Davanture, Mirian Fernández-Vaquero, Chaofan Fan, Jakob Janzen, Yahya Mohammadzadeh, Raphaël Genolet, Nahal Mansouri, Mathias Wenes, Denis Migliorini, Mathias Heikenwälder, Michele De Palma
Abstract
Abstract Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8 + T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.