Senescent fibroblasts promote tumor growth and induce myeloid-derived suppressor cell (MDSC) accumulation in spleen of CT26 tumor bearing mice

SPALLANZANI, RAÚL GERMÁN; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; TORRES, NICOLÁS IGNACIO; ZIBLAT, ANDREA; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; ZWIRNER, NORBERTO WALTER

Mar del Plata

Congreso; 62a Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Sociedad Argentina de Inmunología

As world population becomes older during the next decades, a significant increase in chronic diseases associated with age is expected. In this context, senescence is an ageing-associated phenomenon that involves, among other events, irreversible cell cycle arrest and the secretion of a wide variety of soluble factors, including cytokines, chemokines and growth factors that under certain conditions induce chronic inflammation and promote tumor progression. It has been proposed that senescent fibroblasts directly facilitate tumor growth in immunodeficient mice by promoting epithelial cell proliferation, the production of Vascular Endothelial Growth Factor and Matrix Metalloproteinases. As the effect of senescent stroma on immunesurveillance -a crucial feature that determines tumor progression-, is still unknown, we explored whether senescent fibroblasts favors tumor growth by modulating different immune cell populations such as MDSCs, T regulatory cells (T regs), NK cells, conventional CD4 and CD8 T cells both locally and systemically. To this end, we co-injected CT26 tumor cells along with untreated (CT26+control fb) or etoposide-induced senescent (CT26+senescent fb) IZA-1 cells. We observed a more rapid tumor volume increase in animals from the CT26+senescent fb group compared to controls. This difference (186.8±28.8 mm3 vs 85.5± 2.5 mm3; p<0.05) was detected as early as 10 days after tumor challenge. Moreover, although no significant difference was observed in the intratumoral immune cell infiltrate (T regs, MDSCs, NK cells, CD4 or CD8 T cells) around day 18, such differences in the tumor volume in CT26+senescent fb mice (596.3±12.8 mm3 vs 76.8±38.3 mm3; p<0.01) were associated with a higher percentage of spleen MDSCs compared to control (9.3±1.7 vs 5.1±0.7; p<0.05). Our results indicate that senescent fibroblasts early stimulate tumor growth and this increased neoplastic mass is associated with an expansion of MDSCs in spleen.