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 in murine 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. Conventional CD103+ DCs are critical APCs for cross-presentation of tumor antigens. Sharma and colleagues show that a potent population of Batf3-dependent, CD103+ cross-presenting APCs can arise during tumor immunotherapy via direct differentiation of immature monocytic precursors present in the peripheral MDSC pool.
Bibliographical noteFunding Information:
D.H.M. and B.R.B. have intellectual property interests in the therapeutic use of IDO inhibitors. D.H.M. receives consulting income and research support from NewLink Genetics, Inc.
The authors thank Dr. Ron DePinho for Pten-flox mice; Dr. Miyuki Azuma for PD-L1 antibody clones; Dr. Tasuku Honjo and Hideo Agita for PD-1 and PD-L2 antibody clones; and Anita Sharma, Kimberly Smith, Joyce Wilson, Gabriela Pacholczyk, and Jeanene Pihkala for expert technical assistance. Supported by NIH R01 CA103320 and CA211229 to D.H.M.
© 2017 Elsevier Inc.
- dendritic cells
- myeloid-derived suppressor cells
- tumor immunology