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

Madhav D. Sharma, Paulo C. Rodriguez, Brent H. Koehn, Babak Baban, Yan Cui, Gang Guo, Michiko Shimoda, Rafal Pacholczyk, Huidong Shi, Eun Joon Lee, Hongyan Xu, Theodore S. Johnson, Yukai He, Taha Mergoub, Christopher Venable, Vincenzo Bronte, Jedd D. Wolchok, Bruce R. Blazar, David H. Munn

Research output: Contribution to journalArticle

29 Scopus citations

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 languageEnglish (US)
Pages (from-to)91-106.e6
JournalImmunity
Volume48
Issue number1
DOIs
StatePublished - Jan 16 2018

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Keywords

  • Batf3
  • CD103
  • MDSC
  • PTEN
  • cDC
  • cancer
  • dendritic cells
  • immunotherapy
  • myeloid-derived suppressor cells
  • p53
  • tumor immunology

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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