Alex, C. | Search bioRxiv

bioRxiv2024

Oncolytic vaccinia virus as a precision cancer vaccine platform

Oncolytic viruses are immunotherapeutic agents that selectively replicate in and kill tumour cells with the goal of promoting anti-cancer immune responses. Vaccinia virus (VACV) is a strong oncolytic virus candidate as it infects a wide range of cancer cells, is amenable to genetic tailoring and induces potent, long-lasting immunity. Here, we examine the use of genetically engineered oncolytic VACVs (oVACV) to express a variety of MHC-I complexes and the co-stimulatory ligand CD80 to stimulate anti-tumour CD8+ T cell responses in two syngeneic cancer models. Tumour antigen specific CD8+ T cells were detected in both the tumour and spleen following oVACV treatment, demonstrating the ability to induce tumour targeted T cell responses with viral therapy. oVACV expression of peptide-MHC-I complexes enhanced the efficacy of primary tumour clearance with tumour specific antigen targeting showing the greatest efficacy. Initial tumour clearance following treatment with oVACVs led to variable anti-tumour immune memory depending on the tumour model. Depletion of CD8+ T cells prevented therapeutic efficacy of oVACV while combination with PD-L1 immune checkpoint blockade enhanced tumour clearance. Overall, we demonstrate the ability to generate an oncolytic virus capable of inducing recognition and elimination of tumour cells through VACV-mediated expression of defined peptide-MHC-I complexes.

immunology↗

bioRxiv2020

Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimers disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on {beta}-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6-9 month old wild type and TgF344-AD rats, we discovered that loss of LC-NA axons co-insides with heightened {beta}-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG) that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires {beta}-ARs, and pharmacological blockade of {beta}-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on {beta}-ARs in both behaviors. Thus, a compensatory increase in {beta}-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory. Significance StatementThe locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimers disease pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of {beta} adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.

neuroscience↗