Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L

Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors i...

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Published in:	Cell death & disease Vol. 5; no. 11; p. e1507
Main Authors:	Ramello, M C, Tosello Boari, J, Canale, F P, Mena, H A, Negrotto, S, Gastman, B, Gruppi, A, Acosta Rodríguez, E V, Montes, C L
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-11-2014 Springer Nature B.V Nature Publishing Group
Subjects:	13/106 13/31 14/19 631/250/1619/554 631/250/256 631/67 631/80/86 Antibodies Biochemistry Biomedical and Life Sciences CD4-Positive T-Lymphocytes - cytology CD4-Positive T-Lymphocytes - metabolism CD40 Ligand - genetics CD40 Ligand - metabolism CD8-Positive T-Lymphocytes - cytology CD8-Positive T-Lymphocytes - metabolism Cell Biology Cell Communication Cell Culture Cell Survival Cellular Senescence Coculture Techniques Cytokines - biosynthesis Cytokines - secretion Gene Expression Regulation GPI-Linked Proteins - genetics GPI-Linked Proteins - metabolism HeLa Cells Hepatitis A Virus Cellular Receptor 2 Humans Immunology Lectins, C-Type - genetics Lectins, C-Type - metabolism Life Sciences Mannose-Binding Lectins - genetics Mannose-Binding Lectins - metabolism Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Monocytes - cytology Monocytes - metabolism Nitric Oxide - metabolism Original original-article Primary Cell Culture Reactive Oxygen Species - metabolism Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Receptors, IgG - genetics Receptors, IgG - metabolism Signal Transduction Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism
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Summary:	Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors induce senescence of T cells, which are powerful suppressors of lympho-proliferation. In this study, we report that Tumor-Induced Senescent (TIS)-T cells may also modulate monocyte activation. To gain insight into this interaction, CD4+ or CD8+TIS-T or control-T cells were co-incubated with autologous monocytes under inflammatory conditions. After co-culture with CD4+ or CD8+TIS-T cells, CD14+ monocytes/macrophages (Mo/Ma) exhibit a higher expression of CD16+ cells and a reduced expression of CD206. These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma. TIS-T modulated-Mo/Ma show a higher production of pro-inflammatory cytokines (TNF, IL-1 β and IL-6) and angiogenic factors (MMP-9, VEGF-A and IL-8) and a lower IL-10 and IP-10 secretion than monocytes co-cultured with controls. The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival. Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact. Although CD4+ shows different behavior from CD8+TIS-T cells, blocking mAbs against T-cell immunoglobulin and mucin protein 3 and CD40 ligand reduce pro-inflammatory cytokines and angiogenic factors production, indicating that these molecules are involved in monocyte/macrophage modulation by TIS-T cells. Our results revealed a novel role for TIS-T cells in human monocyte/macrophage modulation, which may have deleterious consequences for tumor progression. This modulation should be considered to best tailor the immunotherapy against cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/cddis.2014.451