Activation of p53 in Immature Myeloid Precursor Cells Controls Differentiation into Ly6c+CD103+Monocytic Antigen-Presenting Cells in Tumors

CD103(+) dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose inmurine tumors via direct differentiation of Ly6c(+) monocytic precursors. These Ly6c(+)CD103(+) cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c(+)CD103(+) phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6c(+)CD103(+) population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6c(+)CD103(+) cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6c(+)CD103(+) monocytic cells represents a potent and previously unrecognized target for immunotherapy.