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

• 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
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.451

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.