Senescent fibroblasts interfere with the tumor immune response in humanized models by inducing neutrophil extracellular traps
Barrera, M. C.; Sonn, A.; Galindo, C. C.; Nehmo, G. M.; Le, O.; Ferbeyre, G.; Beausejour, C.
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Neutrophils are known to promote tumor progression and metastasis, in part through the release of extracellular traps (NETs), a phenomenon associated with poor prognosis in patients. Here, we demonstrate that senescent fibroblasts, via their senescence-associated secretory phenotype (SASP), promote the recruitment of CD33+ myeloid cells and impair the tumor immune response in an orthotopic humanized mouse lung cancer model. Mechanistically, we found that therapy-induced senescence triggers the formation of NETs, which interfere with immune cell infiltration in tumor spheroids. This phenotype was reversible upon treatment with DNAse I or Reparixin, an inhibitor of the action of CXCL8/IL-8 and CXCL1/GRO1, two key SASP factors. Furthermore, we show that senescence-induced NETs favor lung metastasis in a humanized mouse model, a phenotype that was inhibited by DNase I treatment. Our findings provide critical insights into the complex interplay between cellular senescence, NETosis, and the tumor immune response, highlighting another mechanism by which senotherapies can improve cancer treatments.
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