Tumor-induced senescent T (TIST-T) cells: a dysfunctional T cell population with immunomodulatory potential

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

Congreso; LVII Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Senescent T cells are reported to be increased in patients with cancer. Previously, we have demonstrated that CD4+ and CD8+ T cells from healthy donors, after in vitro co-incubation with a tumor cell line, undergo senescence characterized by the loss of costimulatory molecules expression (CD27-CD28-) and telomere shortening. Herein we show that CD4+ and CD8+ tumor-induced senescent T (TIS-T) cells were unable to produce cytokines such as IL-2, IFNg and TNF after polyclonal stimulation. Although CD8+ control T cells (T cells without tumor co-incubation) and CD8+ TIS-T cells showed similar intracellular expression of granzymes B and A, degranulation in CD8+ TIS-T cells was significantly lower than in CD8+ control T cells after PMA/Ionomycin stimulation (p=0.024). In concordance, we observed that CD4+ and CD8+ TIS-T cells significantly down-regulated the expression of TCR-CD3 zeta-chain (p<0.01 vs. control T cells, in both cases), indicating that TCR-signaling is also impaired. In addition, CD4+ and CD8+ TIS-T cells did not express Blimp-1, and CD8+ TIS-T cells did not express Eomes as well. Furthermore, although T-bet was expressed in CD4+ and CD8+ TIS-T cells, they showed lower levels than control T cells. We also found that, CD4+ and CD8+ TIS-T cells completely down-regulated CD62L expression (p<0.01 vs. control T cells, in both cases). Altogether, these results indicate that CD4+ and CD8+ TIS-T cells represent a dysfunctional T cell population. Analyzing the expression of modulatory molecules, we found that CD4+ and CD8+ TIS-T cells expressed higher levels of inhibitory receptors like Tim-3 and KLRG-1 but not PD-1. Interestingly, CD4+ and CD8+ TIS-T cells also expressed higher surface levels of E-cadherin (KLRG-1 ligand), galectin-9 (Tim-3 ligand) and PD-L1 (PD-1 ligand), suggesting that TIS-T cells may modulate themselves and may also regulate other immune cell subsets.