Biology subjects

Le, O.

Publications and source records attributed to Le, O..

3 recordsLinked to original sources

bioRxiv2026

Senescent fibroblasts interfere with the tumor immune response in humanized models by inducing neutrophil extracellular traps

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.

cell biology↗

bioRxiv2024

Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models

Syngeneic mouse tumor models have shown that senescence influences the tumor immune response in multiple ways, including the induction of an immunosuppressive microenvironment or the promotion of immune cell recruitment. Yet, the impact of senescence on the tumor immune response in a humanized setting remains largely unexplored. To address this, we employed tumor spheroids and mice bearing tumors immunogenic to human immune cells derived from the same donor. We found that senescent fibroblasts exert a dual effect by enhancing the recruitment of immune cells into the tumor microenvironment while simultaneously promoting the apoptosis of T and NK cells. Mechanistically, we demonstrate that this apoptosis is primarily due to increased Fas ligand (FasL) expression on the surface of senescent fibroblasts. Deletion of FasL on fibroblasts was sufficient to prevent immune cell death and increase tumor cell killing. Our results highlight the importance of evaluating the impact of therapy-induced senescence in humanized models to understand and predict the outcome of cancer treatments.

cancer biology↗

bioRxiv2021

Autologous humanized mouse models of iPSC-derived tumors allow for the evaluation and modulation of cancer-immune cell interactions

Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or iPSC-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that either fibroblastic, hepatic or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cell suggesting rapid establishment of an immunosuppressive microenvironment. Inhibition of PD-1 by Nivolumab in humanized mice resulted in an increased immune cell infiltration and a slight decrease in tumor growth. We expect these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types. SIGNIFICANCE STATEMENTPreclinical models capable of providing an environment where human tumors are confronted with autologous immune cells are not easily accessible and limit drug development. As an alternative we generated genetically-defined tumor cell lines from primary and iPSC-derived cells for the evaluation of cancer-immune cell interactions in autologous humanized mice.

cancer biology↗