Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 91-106.e6 |
Journal | Immunity |
Volume | 48 |
Issue number | 1 |
DOIs | |
State | Published - Jan 16 2018 |
Bibliographical note
Funding 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.
Funding Information:
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.
Publisher Copyright:
© 2017 Elsevier Inc.
Keywords
- Batf3
- CD103
- MDSC
- PTEN
- cDC
- cancer
- dendritic cells
- immunotherapy
- myeloid-derived suppressor cells
- p53
- tumor immunology