Tumor induced senescent T cells (TIST) promote the production of pro-inflammatory cytokines and angiogenic factors by human monocytes through a cell to cell contact mechanism

RAMELLO MC; TOSELLO BOARI J; CANALE F; ACOSTA RODRIGUEZ EV; MONTES CL

Congreso; First Argentinean Spring Course in Advance Immunology and LXI Reunión Anual de la Sociedad Argentina de Inmunología.; 2013

We demonstrated that a high percentage of human CD4+ or CD8+ T cells from healthy donors incubated with different tumor cell lines in vitro and then cultured for 7 days lose the expression of CD28 and CD27 and express Tim-3, PD-1 and CD40L. These cells do not produce IL-2, IFNg and TNF; a phenotype of senescent/exhausted T cells commonly increased in patients with different cancer and chronic infections. We hypothesize that after infiltrating the tumor mass, senescent T cells modulate other tumor-infiltrating cells like macrophages (Mo) and this may impact in the antitumoral response. To study this, autologous Mo were co-incubated with CD4+ or CD8+ TIST or controls (CD4+ or CD8+ T cells without tumor co-incubation). After LPS stimulation, we evaluated cytokines in supernatant. Mo cultured with CD4+ and CD8+ TIST showed higher production of pro-inflammatory cytokines (TNF, IL-1b and IL-6) and a lower production of IL-10 than Mo co-incubated with controls (p<0.05 for all cases). The study of molecules involved in invasion, angiogenesis and metastasis showed that Mo cultured with CD4+ and CD8+ TIST produced higher levels of MMP-9, VEGF-A and IL-8 than controls (p<0.05 for all cases) and a lower amount of the angiostatic factor IP-10 (p<0.001). Transwell assays showed that Mo-modulation induced by TIST cells requires cell-to-cell contact; in fact the production of IL-8, VEGF-A, IL-6 and IL-1b were reduced in the presence of blocking mAb against Tim-3 and CD40L in CD4+ TIST-Mo co-cultures (p<0.05 in all cases), while in CD8+ TIST-Mo co-cultures the blockade significantly reduced IL-8, VEGF-A and TNF production (p<0.05 in all cases). These results demonstrate that TIST-modulated Mo produce inflammatory cytokines and factors involved in angiogenesis which may have deleterious consequences for antitumoral response