Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy

Dendritic cells (DCs) are specialized myeloid cells with the ability to uptake, process, and present antigens to T lymphocytes. They also generate cytokine and chemokine gradients that regulate immune cell trafficking, activation, and function. Monocyte-derived DCs (moDCs) pulsed with tumor antigens have been used as a platformfor therapeutic vaccination in cancer. However, in spite of significant development and testing, antigen-loaded moDCs have delivered mixed clinical results. In my thesis, I have worked on a new DC therapy approach that uses a population named DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. In the absence of antigen loading, cytokine-armed DCPs efficiently differentiated into conventional type I DCs (cDC1) and inhibited tumor growth in melanoma and autochthonous liver cancer models. Tumor response to DCP therapy involved synergy between IL-12 and FLT3L and was associated with massive effector T cell infiltration and NK cell activation, robust M1-like macrophage programming, and ischemic tumor necrosis. Mechanistically, anti-tumor immunity was dependent on endogenous cDC1 expansion and interferon-y (IFN-y) production and signaling, but did not require CD8+ T cell cytotoxicity. In one application, cytokine-armed DCPs synergized with antigen-specific CAR-T cells to eradicate intracranial gliomas in mice.