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

doi:10.1016/j.immuni.2017.12.014

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

Immunity. 2018 Jan 16;48(1):91-106.e6. doi: 10.1016/j.immuni.2017.12.014.

Authors

Madhav D Sharma¹, Paulo C Rodriguez², Brent H Koehn³, Babak Baban⁴, Yan Cui⁵, Gang Guo⁵, Michiko Shimoda², Rafal Pacholczyk², Huidong Shi⁵, Eun-Joon Lee⁵, Hongyan Xu⁶, Theodore S Johnson¹, Yukai He², Taha Mergoub⁷, Christopher Venable², Vincenzo Bronte⁸, Jedd D Wolchok⁷, Bruce R Blazar³, David H Munn⁹

Affiliations

¹ Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
² Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
³ Department of Pediatrics and Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.
⁵ Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
⁶ Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Population Health Science, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
⁷ Department of Medicine, Immunology Program and Ludwig Center, Memorial Sloan Kettering Cancer Center; Weill Cornell Medical School and Graduate School of Biomedical Sciences; and Ludwig Institute for Cancer Research, New York, NY 10065, USA.
⁸ University Hospital and Department of Medicine, University of Verona, Verona 37134, Italy.
⁹ Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address: dmunn@augusta.edu.

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.

Keywords: Batf3; CD103; MDSC; PTEN; cDC; cancer; dendritic cells; immunotherapy; myeloid-derived suppressor cells; p53; tumor immunology.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigen-Presenting Cells / immunology
Antigen-Presenting Cells / physiology*
Antigens, CD / metabolism
Antigens, Ly / metabolism
Cell Differentiation / genetics
Cell Differentiation / physiology
Cell Line
Flow Cytometry
Humans
Immunotherapy / methods
Integrin alpha Chains / metabolism
Mice
Monocytes / immunology
Monocytes / physiology*
Myeloid Cells / metabolism*
Myeloid Cells / physiology
Neoplasms / immunology*
Tumor Suppressor Protein p53 / metabolism*

Substances

Antigens, CD
Antigens, Ly
Integrin alpha Chains
Ly-6C antigen, mouse
Tumor Suppressor Protein p53
alpha E integrins

Abstract

Publication types

MeSH terms

Substances

Grants and funding