Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells

Abstract

Summary: Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1+ dendritic cells to enhance CD8+ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade. : Tsuchiya et al. demonstrate that local administration of iPSC-derived myeloid cells producing interferon-α suppresses local, as well as distant, tumors. The efficacy depends on the tumor-reactive T cell response mediated by the activation of host XCR1+ dendritic cells. The concomitant use of a PD-1/PD-L1 inhibitor yields a superior antitumor effect. Keywords: cancer immunotherapy, induced pluripotent stem cells, type I interferon, XCR1, dendritic cells, cross-presentation, checkpoint blockade, PD-1, STING, CXCR3