CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
artículos
Título:
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
Autor/es:
RAMELLO MC; TOSELLO BOARI J; CANALE FP; MENA HP; NEGROTTO S; GASTMAN B; GRUPPI A; ACOSTA RODRIGUEZ EV; MONTES CL
Revista:
Cell Death & Disease
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Año: 2014
ISSN:
2041-4889
Resumen:
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, monocytes/macrophages exhibit a high percentage of CD14+CD16+ cells and a reduced expression of CD206. These monocytes/macophages produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of monocytes/macrophages. TIS-T modulated-monocytes/macrophages show a higher production of pro-inflammatory cytokines (TNF, IL-1 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-macrophages 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 Tim-3 and CD40L 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 in order to best tailor the immunotherapy against cancer.