DEFECTIVE NK CELL ACTIVATION, MACROPHAGE POLARIZATION AND TUMOR GROWTH CONTROL IN A SENESCENT ENVIRONMENT.

MARÍA NATALIA RUBINSZTAIN; MARÍA VICTORIA REGGE; MARIANA GANTOV; MARÍA CECILIA SANTILLI; ADRIÁN DAVID FRIEDRICH; ALDANA TROTTA; JESSICA MARIEL SIERRA; FLORENCIA SECCHIARI; BELÉN CANDELA LOZADA MONTANARI; JULIETA ERRAMOUSPE; MERCEDES BEATRIZ FUERTES; CAROLINA INÉS DOMAICA; NORBERTO WALTER ZWIRNER,

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias. SAIC. SAI&FAIC. SAFIS. 2022; 2022

SAIC. SAI&FAIC. SAFIS.

Ageing is associated with the accumulation of senescent cells, development of many typesof cancer, and defective immune responses against infection, vaccines and neoplastic cells.However, the effect of such accumulation on the immune system remains ill-defined. Thus,this work aimed to analyze the effects of senescent non-immune cells (fibroblasts) on NKcell IFN-γ production, macrophage polarization and tumor growth. To generate senescentfibroblasts (SenFb), the IZA non-tumorigenic mouse fibroblast cell line was treated with 1µMof etoposide for 48 h. After removal of etoposide and culture for 24 h, SenFb and controlfibroblasts (ConFb) were cocultured with spleens of normal syngeneic (BALB/c) mice in thepresence of IL-12, IL-15 and IL-18 for 24 h or with bone marrow-derived macrophages(obtained by culture of bone marrow cells with M-CSF for 5 days) in the absence or in thepresence of M1-, M2- and tumor-associated macrophage (TAM)-like polarizing conditions for48 h (LPS and IFN-γ for M1 polarization, IL-4 and IL-13 for M2 polarization, and conditionedmedia from the CT26 syngeneic tumor cell line) for 48 h. SenFb led to a significant decreasein the frequency of IFN-γ-producing NK cells, as assessed by flow cytometry (FC; SenFb:media 44.3±4.4, ConFb: 66.7±2.4, n= 15, p<0.001). Also, SenFb induced an increase in theexpression of the M2-associated marker CD206 in the presence of M1 polarizing conditions(CD206 MFI: SenFb: 204.3±13.3, ConFb: 52.0± 4.5, n=3, p<0.05). A similar trend wasobserved in M2 and TAM-like polarizing conditions. In line with these findings, the coloncarcinoma cell line CT26 exhibited an accelerated in vivo growth when they were coinjectedwith SenFb compared to ConFb. Our results indicate that a senescent environmentnegatively affects NK cell IFN-γ production, and macrophage polarization, resulting in fastertumor growth, providing a possible explanation for the increased frequency of malignanciesobserved in the elderly.