Senescent fibroblasts crosstalk with myeloid cells to negatively regulate NK cell-mediated IFN-gamma production. Impact on tumor growth.

ARAYA ROMINA ELIZABETH; SPALLANZANI RAUL GERMAN ; RAFFO IRAOLAGOITIA XIMENA LUCÍA; TORRES NICOLÁS IGNACIO; ZIBLAT ANDREA; NUÑEZ SOL YANEL; SIERRA JESSICA MARIEL; DOMAICA CAROLINA INÉS; FUERTES MERCEDES BEATRIZ; ZWIRNER NORBERTO WALTER

Ciudad Autónoma de Buenos Aires

Congreso; LXIII Argentinean Immunology Society Meeting; 2015

Sociedad Argentina de Inmunología

Chronic diseases including cancer significantly increase during ageing. Ageing is associated with accumulation of senescent cells that display a senescence-associated secretory phenotype that promotes chronic inflammation and favors tumor progression. Previous own results demonstrated that a senescent environment stimulates tumor growth and expands myeloid-derived suppressor cells (MDSCs) in spleen of CT-26 tumor-bearing BALB/c mice after 18 days. Therefore, early events associated with the senescent environment may shape tumor growth. Accordingly, the aim of this work was to investigate short term effects induced by senescent fibroblasts on innate immunity that may impact tumor progression. BALB/c mice were co-injected with CT26 tumor cells and control (CFb) or senescent (1µM etoposide, 24h) fibroblasts (SFb). After 5 days, mice injected with SFb exhibited decreased percentages of intra-tumoral CD11b+F4/80+ cells (macrophages) with reduced MHC-II and CD86 expression (suggesting a shift towards a M2 phenotype) and diminished IFN-γ production by intra-tumoral NK cells, compared to mice injected with CFb. In vitro experiments demonstrated a reduced percentage of IFN-γ+ NK cells when splenocytes (but not isolated NK cells) from healthy mice were stimulated with IL-12+IL-15+IL-18 in the presence of SFb, suggesting that SFb harness NK cell-mediated IFN-gamma production through an indirect mechanism. Isolated NK cells supplemented with adherent or non-adherent cells from spleens of healthy mice and SFb or CFb demonstrated that such effect was mediated by adherent cells. We conclude that senescent fibroblasts, through a crosstalk with adherent cells (macrophages?), negatively affect NK cell-mediated IFN-gamma production, which impacts on tumor growth.