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 W Pacholczyk, Huidong Shi, Eun Joon Lee, Hongyan Xu, Theodore Samuel Johnson, Yukai He, Taha Mergoub, Christopher Venable, Vincenzo Bronte, Jedd D. Wolchok, Bruce R. Blazar, David H Munn

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages91-106.e6
JournalImmunity
Volume48
Issue number1
DOIs
StatePublished - Jan 16 2018

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Antigen-Presenting Cells
Myeloid Cells
Immunotherapy
Cell Differentiation
Cross-Priming
Neoplasm Antigens
Neoplasms
Population
Dendritic Cells
Transcription Factors
Up-Regulation
Cell Count
Bone Marrow
alpha E integrins
Inflammation
Phenotype
Drug Therapy
Pharmaceutical Preparations
Myeloid-Derived Suppressor Cells

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Activation of p53 in Immature Myeloid Precursor Cells Controls Differentiation into Ly6c+CD103+ Monocytic Antigen-Presenting Cells in Tumors. / Sharma, Madhav D; Rodriguez, Paulo C.; Koehn, Brent H.; Baban, Babak; Cui, Yan; Guo, Gang; Shimoda, Michiko; Pacholczyk, Rafal W; Shi, Huidong; Lee, Eun Joon; Xu, Hongyan; Johnson, Theodore Samuel; He, Yukai; Mergoub, Taha; Venable, Christopher; Bronte, Vincenzo; Wolchok, Jedd D.; Blazar, Bruce R.; Munn, David H.

In: Immunity, Vol. 48, No. 1, 16.01.2018, p. 91-106.e6.

Research output: Contribution to journalArticle

Sharma, Madhav D ; Rodriguez, Paulo C. ; Koehn, Brent H. ; Baban, Babak ; Cui, Yan ; Guo, Gang ; Shimoda, Michiko ; Pacholczyk, Rafal W ; Shi, Huidong ; Lee, Eun Joon ; Xu, Hongyan ; Johnson, Theodore Samuel ; He, Yukai ; Mergoub, Taha ; Venable, Christopher ; Bronte, Vincenzo ; Wolchok, Jedd D. ; Blazar, Bruce R. ; Munn, David H. / Activation of p53 in Immature Myeloid Precursor Cells Controls Differentiation into Ly6c+CD103+ Monocytic Antigen-Presenting Cells in Tumors. In: Immunity. 2018 ; Vol. 48, No. 1. pp. 91-106.e6.
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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.",
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AU - Baban, Babak

AU - Cui, Yan

AU - Guo, Gang

AU - Shimoda, Michiko

AU - Pacholczyk, Rafal W

AU - Shi, Huidong

AU - Lee, Eun Joon

AU - Xu, Hongyan

AU - Johnson, Theodore Samuel

AU - He, Yukai

AU - Mergoub, Taha

AU - Venable, Christopher

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AU - Wolchok, Jedd D.

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AB - 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.

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