Research Reports

Datopotamab deruxtecan induces hallmarks of immunogenic cell death

Sabrina Forveille^1,2, Marion Leduc^1,2, Allan Sauvat^1,2, Guido Kroemer^1,2,3and Oliver Kepp^1,2

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A versatile method for the identification of senolytic compounds

Chiara Annunziata¹, Francesca Castoldi¹, Jan Schlegel², Hazel X. Ang¹, Mina Ristovska¹, Stefania Melini³, Robert Welch⁴, Christian G. Riedel¹ and Federico Pietrocola¹

The increased burden of senescent cells is as a well-established hallmark of aging and age-related diseases. This finding sparked significant interest in the identification of molecules capable of selectively eliminating senescent cells, so-called senolytics. Here, we fine-tuned a method for the identification of senolytics that is compatible with high-content fluorescence microscopy. We used spectral detector imaging to measure the emission spectrum of unlabeled control or senescent cells. We observed that senescent cells exhibited higher levels of autofluorescence than their non-senescent counterparts, particularly in the cytoplasmic region. Building on this result, we devised a senolytic assay based on co-culturing quiescent and senescent cells, fluorescently tagged in the nuclear region through the overexpression of H2B-GFP and H2B-RFP, respectively. We validated this approach by showing that first generation senolytics were effective in reducing the (...)

MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in MYCN-amplified neuroblastoma

Konstantinos V. Floros¹, Ayesha T. Chawla¹, Mia O. Johnson-Berro¹, Rishabh Khatri¹, Angeliki M. Stamatouli², Sosipatros A. Boikos³, Mikhail G. Dozmorov⁴, L. Ashley Cowart^5,6 and Anthony C. Faber¹

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in MYCN-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of SLC3A2 (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is (...)

Inflammation induced PD-L1-specific T cells

Shamaila Munir¹, Mia Thorup Lundsager¹, Mia Aabroe Jørgensen¹, Morten Hansen¹, Trine Hilkjær Petersen², Charlotte Menne Bonefeld², Christina Friese¹, Özcan Met^1,2, Per thor Straten^1,2 and Mads Hald Andersen^1,2,3

PD-L1-specific T cells are a natural part of the T-cell repertoire in humans. Hence, we have previously described spontaneous CD8+ and CD4+ T-cell reactivity against PD-L1 in the peripheral blood of patients with various cancers as well as in healthy donors. It is well described that the expression of the PD-L1 protein is introduced in cells by pro-inflammatory cytokines, e.g. IFN-γ. In the current study, we were able to directly link inflammation with PD-L1-specific T cells by showing that inflammatory mediators such as IFN-γ generate measurable numbers of PD-L1-specific T cells in human PBMCs as well as in in vivo models. These PD-L1-specific T cells can vigorously modulate the cell compartments of the local environment. PD-L1-specific T cells may be important for immune homeostasis by sustaining the ongoing inflammatory response by the suppression of regulatory cell function both (…)

Neuronal Lamin regulates motor circuit integrity and controls motor function and lifespan

Lisa J. Oyston^1,2,3, Yong Qi Lin¹, Thang M. Khuong¹, Qiao-Ping Wang¹, Man Tat Lau¹, Teleri Clark¹ and G. Gregory Neely¹

Neuronal aging involves a progressive decline in cognitive abilities and loss of motor function. Mutations in human Lamin genes (LMNA, LMNB1, LMNB2) lead to a wide-range of diseases including muscular dystrophy, peripheral neuropathy and progeria. Here we investigate the role of neuronal Lamin in regulating age-related phenotypes. Neuronal targeting of Lamin led to shortened lifespan, progressive impairment of motor function and loss of dopaminergic (DA) neurons within the protocerebral anterior medial (PAM) cluster in the Drosophila melanogaster brain. Loss of neuronal Lamin caused an age-related decline in neural physiology, with slower neurotransmission and increased chance of motor circuit failure with age. Unexpectedly, Lamin-dependent decline in motor function was specific for the chemical synapses of the dorsal longitudinal muscle (DLM). Together (...)