Current lab members:

• Julien CHERFILS-VICINI CRN CNRS
• Dr Laurence Bianchini (researcher CNRS CRHC)
• Dr Berengère Dedone-Montaudie (MD PhD MCU-PH)
• Julian Chamucero-Milares (Post-Doc)
• Iryna Moskalevska (Third year PhD student)
• Raphael Rousset (Alternant Licence Pro 2023/2024)

Lab Alumni:

• Melissa Chapeau (Master 2 2023)
• Coline Eliott (Master 1 2023)

Old age comes with the burden of a host of aging-associated diseases including cancer and Senescent cells (SnCs) accumulation in tissues emerge as a key factor. Therapeutic opportunities to blunt aging and cancer by eliminating SnCs was strongly challenged over the last 10 years. However, despite extremely dynamic research by both academic and private labs, almost all clinical trials are based on anti-cancer drugs repositioning (e.g. anti-apoptosis) and none of them has demonstrated a sufficient beneficial effect.

Our team’s project aims to tackle the burden of age-related diseases, including cancer, by targeting the accumulation of senescent cells (SnCs) in tissues.

In this context, we discovered that SnCs can modulate their immunosurveillance by the expression of a cell surface ganglioside called GD3, resulting in SnCs persistence. (Iltis et al, BioRchiv, in revision for Nature Aging, patent PCT/EP2022/060713 and patent EP22306604). We bring the proof of concept that GD3 expression may represent a Senescence Immune Checkpoint (SIC) that determines SnCs tolerance.

The team aims to reveal a new class of senolytic/senomorphic (anti-SIC strategy) to restore SnCs immunosurveillance and to understand the cellular and molecular mechanisms of senescent cell tolerance by the immune system, as well as their consequences.

The outstanding question we want to address is: What are the cellular and molecular mechanism of senescent cell (SnCs) tolerance by the immune system and what are their consequences?

Our team objectives are to address the cellular and molecular mechanisms of senescence cell (SnCs) tolerance by the immune system and their consequences using cross-discipline approaches where Immunity, Aging, Senescence and Cancer are concomitantly studied.

The overall impact of this team project is double, both at the forefront of basic and translational science to better understand and eventually to propose new cure against age related disease and cancer by restoring immune surveillance.

Current Projects

Top Publications

• Activated B-Cells enhance epitope spreading to support successful cancer immunotherapy
  4 avril 2024 par Guillaume Kellermann
  Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful immunotherapy requires epitope spreading, but the slow or inefficient induction of functional antitumoral immunity delays the benefit to patients or causes resistances. Therefore, understanding the key mechanisms that support epitope spreading is essential to improve immunotherapy. In this review, we highlight the major role played…
• Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation
  10 avril 2023 par Alexandra Mousset
  Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells…
• A Novel Screen for Expression Regulators of the Telomeric Protein TRF2 Identified Small Molecules That Impair TRF2 Dependent Immunosuppression and Tumor Growth
  2 juillet 2021 par Mounir El Maï
  Telomeric repeat-binding factor 2 (TRF2) is a subunit of the shelterin protein complex, which binds to and protects telomeres from unwanted DNA damage response (DDR) activation. TRF2 expression plays a pivotal role in aging and cancer, being downregulated during cellular senescence and overexpressed during oncogenesis. Cancers overexpressing TRF2 often exhibit a poor prognosis. In cancer cells, TRF2 plays multiple functions, including telomere protection and non-cell autonomous roles, promoting…
• Neutrophils: mediating TelOxidation and senescence
  21 avril 2021 par Maria Sol Jacome Burbano
  Cellular senescence is considered to be a major driver of aging, yet the mechanisms explaining the accumulation of senescent cells during life time remain unclear. In this issue, Lagnado et al (2021) show that neutrophils can trigger the senescence of neighboring cells by transmitting reactive oxygen species (ROS), which they normally produce to fight pathogens. The main genomic targets of the neutrophil-mediated ROS damage are telomeres, supporting an intimate interplay between telomere…
• Association of TRF2 expression and myeloid-derived suppressor cells infiltration with clinical outcome of patients with cutaneous melanoma
  2 avril 2021 par Marius Ilié
  The outcome of patients with cutaneous melanoma has been strongly modified by recent advances obtained with Immune Checkpoint Inhibitors (ICIs). However, despite this breakthrough, durable response to ICIs is limited to a subset of patients. We investigated whether the expression of TRF2, which preserves telomere integrity, and have an effect on tumor immunosurveillance notably by directly recruiting and activating myeloid-derived suppressor cells (MDSCs), could be a prognostic biomarker in…
• A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy
  29 janvier 2021 par Laetitia Douguet
  Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates…
• Longevity clocks: The promoting role of telomeres?
  9 décembre 2020 par Julien Cherfils-Vicini
  Aging is an alteration of our physiological capacities that is accompanied by an increased susceptibility to develop a wide range of diseases and which determines in large part our longevity. Despite intensive research on the origin of aging, its etiology is still poorly understood. We discuss here the hypothesis that the telomere shortening, programmed to start at the end of embryogenesis in numerous tissues, couples development with aging by a time-dependent regulation of a set of…
• Inhibiting TRF1 upstream signaling pathways to target telomeres in cancer cells
  6 juillet 2019 par Julien Cherfils-Vicini
  In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: On one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA…
• Cancer cells induce immune escape via glycocalyx changes controlled by the telomeric protein TRF2
  20 avril 2019 par Julien Cherfils-Vicini
  Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan,…
• TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment
  31 janvier 2019 par Pasquale Zizza
  The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angiogenesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping….
• TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection
  18 janvier 2016 par Delphine Benarroch-Popivker
  The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ∼ 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres…
• Genetic and pharmacological inactivation of the purinergic P2RX7 receptor dampens inflammation but increases tumor incidence in a mouse model of colitis-associated cancer
  8 janvier 2015 par Paul Hofman
  Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools,…
• The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression
  17 décembre 2014 par Kay-Dietrich Wagner
  Angiogenesis, activation of metastasis and avoidance of immune destruction are important for cancer progression. These biological capabilities are, apart from cancer cells, mediated by different cell types, including endothelial, haematopoietic progenitor and myeloid-derived suppressor cells. We show here that all these cell types frequently express the Wilms' tumour suppressor Wt1, which transcriptionally controls expression of Pecam-1 (CD31) and c-kit (CD117). Inducible conditional knockout of…
• The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells
  30 juin 2014 par Antoine Marçais
  Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and…
• A novel pathway links telomeres to NK-cell activity: Implications for immunotherapy
  5 avril 2014 par Julien Cherfils-Vicini
  Here, we describe a model in which telomeric repeat-binding factor 2 (TERF2) can control tumorigenesis not only via cancer cell-intrinsic mechanisms but also via non-cancer cell autonomous pathways. Indeed, we have recently shown that TERF2 regulates tissue homeostasis as it promotes the elimination of aged, damaged, and neoplastic cells by the immune system, opening the way to new therapeutic options against cancer.

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