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

ARAYA, ROMINA ELIZABETH; SPALLANZANI, RAÚL GERMÁN; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; TORRES, NICOLÁS IGNACIO; ZIBLAT, ANDREA; NÚÑEZ, SOL YANEL; SIERRA, JESSICA MARIEL; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; ZWIRNER, NORBERTO WALTER

Buenos Aires

Congreso; IV Latinamerican Society for Immunodeficiencies (LASID) Meeting, LXIII Meeting of the Argentinean Society of Immunology and II French-Argentinean Immunology Meeting.; 2015

Latinamerican Society for Immunodeficiencies (LASID) y Sociedad Argentina de Inmunología (SAI)

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