Biology subjects

Craig, H.

Publications and source records attributed to Craig, H..

4 recordsLinked to original sources

bioRxiv2023

Global Pannexin 1-deletion increases tumor-infiltrating lymphocytes in the BRAF/Pten mouse melanoma model.

Immunotherapies for malignant melanoma seek to boost the anti-tumoral response of CD8+ T cells but have a limited patient response rate, in part due to limited tumoral immune cell infiltration. Genetic or pharmacological inhibition of Pannexin 1 (PANX1) channel-forming protein is known to decrease melanoma cell tumorigenic properties in vitro and ex vivo. Here, we crossed Panx1 knockout (Panx1-/-) mice with the inducible melanoma model: BrafCA, PtenloxP, Tyr::CreERT2 (BPC). We found that deleting the Panx1 gene in mice does not reduce BRAF(V600E)/Pten-driven primary tumor formation or improve survival. However, BPC-Panx1-/- mice tumors exhibited a significant increase in infiltration of CD8+ T lymphocytes with no changes in the expression of early T cell activation marker CD69, LAG-3 checkpoint receptor or PD-L1 in tumors when compared to BPC-Panx1+/+ genotype. Our results suggest that although a Panx1 deletion does not overturn the aggressive BRAF/Pten-driven melanoma progression in vivo, it does increase the infiltration of effector immune T cell populations in the tumor microenvironment. We propose that PANX1-targeted therapy could be explored as a strategy to increase tumor-infiltrating lymphocytes to boost anti-tumor immunity.

cancer biology↗

bioRxiv2020

Development of additional microsatellite primers for the mangrove tree species Avicennia germinans

ObjectiveThe objective of this study was to develop additional microsatellite primers for the mangrove tree species Avicennia germinans that work in multiplex PCR panels to enable cost effective population analyses of this species at a finer scale. ResultsPrimer sets were identified from whole genome sequencing data and combined into multiplex PCR panels. Five multiplex reactions containing 20 novel primer sets with trinucleotide repeats were successfully developed. Fifteen of the microsatellite loci were polymorphic in the samples tested, with 1-4 alleles per locus.

genetics↗

bioRxiv2020

Optogenetic activation of CA1 pyramidal neurons in vivo induces hypersynchronous and low voltage fast seizures

Increasing evidence supports the idea that the CA1 of the hippocampus plays an important role in the pathogenesis of temporal lobe epilepsy (TLE). There is however a lack of proof that the over-excitation of CA1 alone is sufficient in inducing seizures in vivo. Furthermore, the relevance of the seizures induced from the over-excitation of CA1 to the pathophysiology of TLE is undetermined. Here, we employed optogenetics to activate pyramidal neurons (PNs) in CA1, which reliably induced generalized seizures in freely moving non-epileptic mice. We showed that repeated photostimulations had a kindling effect. In addition, seizures induced by over-active CA1 PNs were dominated by two distinctive onset patterns, i.e. hypersynchronous (HYP) and low voltage fast (LVF) activities, which are widely recorded in patients with and animal models of TLE. In our study, HYP seizures were predominantly associated with the first photostimulation and were entirely replaced by the LVF type afterwards. This phenomenon suggests that the activation of CA1 PNs, when occurring after the first seizure, could lead to the recruitment of GABAergic interneurons to participate in the seizure generation. These findings suggest that seizures induced from the over-excitation of CA1 PNs likely involved the same hippocampal networks and cellular mechanisms underlying TLE.

neuroscience↗

bioRxiv2019

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression.

The immunosuppressive tumour microenvironment constitutes a significant hurdle to the response to immune checkpoint inhibitors. Both soluble factors and specialised immune cells such as regulatory T cells (TReg) are key components of active intratumoural immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor (ICOS) is highly expressed in the tumour microenvironment, especially on TReg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we used immune profiling of samples from tumour bearing mice and cancer patients to characterise the expression of ICOS in different tissues and solid tumours. By immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that binds ICOS from different species. Using KY1044, we demonstrated that we can exploit the differential expression of ICOS on T cell subtypes to modify the tumour microenvironment and thereby improve the anti-tumour immune response. We showed that KY1044 induces sustained depletion of ICOShigh TReg cells in mouse tumours and depletion of ICOShigh T cells in the blood of non-human primates, but was also associated with secretion of pro-inflammatory cytokines from ICOSlow TEFF cells. Altogether, KY1044 improved the intratumoural TEFF:TReg ratio and increased activation of TEFF cells, resulting in monotherapy efficacy or in synergistic combinatorial efficacy when administered with the immune checkpoint blocker anti-PD-L1. In summary, our data demonstrate that targeting ICOS with KY1044 can favourably alter the intratumoural immune contexture, promoting an anti-tumour response.

cancer biology↗