Biology subjects

Conforti, L.

Publications and source records attributed to Conforti, L..

2 recordsLinked to original sources

bioRxiv2025

Potassium channels mediate the inhibitory effect of exosomes on anti-tumor immunity in head and neck cancer

Head and neck squamous cell carcinomas (HNSCC) are aggressive cancers with a relatively low response rate to immunotherapy. Anti-tumor immune responses rely on cytotoxic T and NK cells infiltrating the tumor microenvironment to eliminate cancer cells. However, tumors activate multiple mechanisms to evade these responses. Tumor-derived small extracellular vesicles, also known as exosomes, reshape the tumor microenvironment by impairing cytotoxic T and NK cell function, promoting immune escape and metastasis. Transcriptomic analysis of healthy donor peripheral blood mononuclear cells (PBMCs) exposed to exosomes from HPV-negative HNSCC patient primary cancer cells revealed reduced cytotoxic cells and suppressed immune responses including cytotoxicity, chemokine production, and NK and T cell functions. Bead-based multiplex immunoassay showed that HNSCC-derived exosomes inhibited the release of effector cytokines (IL-2, TNF-, IFN-{gamma}) and cytotoxic molecules from activated CD8 T cells. While ion channels regulate Ca{superscript 2}-dependent cytotoxicity and cytokine production and release, their role in exosome-mediated immune suppression is unexplored. We found that tumor-derived exosomes selectively inhibit KCa3.1 channel activity in CD8 T cells by downregulating calmodulin, ultimately impairing Ca{superscript 2} signaling and IFN-{gamma} release. This study identifies a novel mechanism of exosome-mediated immunosuppression, positioning KCa3.1 as a promising therapeutic target to enhance immune surveillance and immunotherapy response in HNSCC.

immunology↗

bioRxiv2019

Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinsons disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

neuroscience↗