Defective NK cell activation, macrophage polarization and tumor growth control in a senescent environment

RUBINSZTAIN, NATALIA; REGGE, MARÍA VICTORIA; GANTOV, MARIANA; SANTILLI, M. CECILIA; FRIEDRICH, ADRIÁN D.; TROTTA, ALDANA; SIERRA, JESSICA M.; SECCHIARI, FLORENCIA; LOZADA MONTANARI, BELEN C.; ERRAMOUSPE, JULIETA; FUERTES, MERCEDES B.; DOMAICA, CAROLINA I.; ZWIRNER, NORBERTO W.

Mar del Plata

Congreso; Reunión Conjunta SAIC SAI FAIC SAFIS; 2022

Ageing is associated with the accumulation of senescent cells, development of many types of 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 NK cell IFN-γ production, macrophage polarization and tumor growth. To generate senescent fibroblasts (SenFb), the IZA non-tumorigenic mouse fibroblast cell line was treated with 1µM of etoposide for 48 h. After removal of etoposide and culture for 24 h, SenFb and control fibroblasts (ConFb) were cocultured with spleens of normal syngeneic (BALB/c) mice in the presence 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 the presence of M1-, M2- and tumor-associated macrophage (TAM)-like polarizing conditions for 48 h (LPS and IFN-γ for M1 polarization, IL-4 and IL-13 for M2 polarization, and conditioned media from the CT26 syngeneic tumor cell line) for 48 h. SenFb led to a significant decrease in 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