Activation of p53 in immature myeloid precursor cells controls differentiation into Ly6c(+)CD103(+) monocytic antigen-presenting cells in tumors Journal Article

   

Authors:	Sharma, M. D.; Rodriguez, P. C.; Koehn, B. H.; Baban, B.; Cui, Y.; Guo, G.; Shimoda, M.; Pacholczyk, R.; Shi, H.; Lee, E. J.; Xu, H.; Johnson, T. S.; He, Y.; Mergoub, T.; Venable, C.; Bronte, V.; Wolchok, J. D.; Blazar, B. R.; Munn, D. H.
Article Title:	Activation of p53 in immature myeloid precursor cells controls differentiation into Ly6c(+)CD103(+) monocytic antigen-presenting cells in tumors
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 inmurine 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:	chemotherapy; melanoma; dendritic cells; in-vivo; immunity; macrophages; expression; t-cells; responses; suppressor-cells; anticancer
Journal Title:	Immunity
Volume:	48
Issue:	1
ISSN:	1074-7613
Publisher:	Cell Press
Date Published:	2018-01-16
Start Page:	91
End Page:	106.e6
Language:	English
ACCESSION:	WOS:000422751600013
DOI:	10.1016/j.immuni.2017.12.014
PROVIDER:	wos
PUBMED:	29343444
PMCID:	PMC6005382
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/120904