Overview
Develop knowledge of the immune system involvement in canine glioma and MUO (see below), with translation to comparable human diseases, utilizing complimentary techniques including flow cytometry, RNA-seq, clinical assessment tools and MRI radiomics.
About this opportunity
The immune system plays a pivotal role in both canine glioma and meningo-encephalitis of unknown origin (MUO).
High-grade glioma is recurrent, terminal, and incompletely understood in dogs and people. This problem is most intense with glioblastoma. As one of the cancers with the very worst median survival, new therapies are desperately needed. This demands discovery of novel treatment targets.
The immune system has important roles in brain cancer progression and resistance to traditional therapies, and is now being harnessed in emerging glioma therapies. Gliomas in dogs are emerging as a human neuro-oncological model, having already been successfully leveraged in the development of several immunotherapies for human patient use. The immune landscape and tumour microenvironment (TME) of glioma in dogs display considerable overlap with human glioma. However, a considerable knowledge gap remains in our understanding of the canine glioma TME. Furthermore, traditional cell quantification techniques (i.e. flow cytometry) are antibody-dependent. This limits direct translational
between species (e.g. human and canine), and antibody binding prevents certain additional analyses of the isolated cell populations.
MUO is one of the most common brain diseases of dogs, consisting of various, apparently immune-mediated, encephalitides (GME, NME, NLE, etc.). MUO may serve as a model of human autoimmune encephalitis or multiple sclerosis. The condition remains fatal in around one-third of affected dogs. Current knowledge gaps in MUO involve the optimum therapy, how to prognosticate and personalize therapy, and how to objectively measure outcome. It is not currently known which cases should receive adjunctive medications in addition to glucocorticoids, in part because measuring outcome remains problematic. Further, CSF analysis plays a major role in the diagnosis of MUO, but is currently limited to traditional analysis including cytology, and may represent a missed opportunity in ante-mortem evaluation. The aetiology, ante-mortem diagnosis of sub-type (GME, NME, etc.), the prognostication and the quantification of treatment response are all in need of major improvement.
Our previous work has established that a complex immunosuppressive TME exists in canine glioma, with many similarities to human glioma / glioblastoma. Both influxes of inflammatory anti-tumour calls (neutrophils, M1 macrophages) and influx of anti-inflammatory cells (regulatory T cells, M2 macrophages) were seen, resulting in decreases in key anti-tumour effector cells (CD8+ lymphocytes, T follicular helper cells).
We have also developed the NDS (Neuro-Disability Scale) for use in MUO, and investigated for both clinical and MRI risk factors for outcome and disability. A higher NDS was associated with decreased survival, highlighting the utility of clinical grading instruments. Similarly, lesion loads on MRI (T2 and T1 post-contrast) were associated with decreasing survival and increasing relapse, respectively.
This PhD is an exciting collaboration between the Institute of Infection, Veterinary and Ecological Sciences (IVES) and the Technology, Infrastructure and Environment Directorate. The aims of this PhD studentship are to investigate the immunological system in canine glioma and MUO, utilizing peripheral blood, CSF, surgical and post-mortem tissue. We will compare immuno-analyses with established techniques such as flow cytometry, RNA-seq, MRI, pathology and clinical pathology, and outcome analyses. Outcome analyses will be developed, including establishing or modifying the NDS in brain tumour cases, and caregiver tools. Dependent on equipment availability, there may be potential to develop an antibody-free alternative to flow cytometry.
Techniques to be developed during this study:
-Flow cytometry, RNA-seq and CIBERSORT, novel “antibody-free flow cytometry”
-Comparisons with MRI, histology and immunohistochemistry
-Clinical outcome analyses – owner-reported and clinical assessments
The anticipated outputs of this study include tools to assess disease burden in canine brain tumours and MUO, including expansion of the NDS, MRI radiomics, and peripheral blood immuno-analyses. The study of immune perturbations in canine glioma could lead to the detection of translational immunological treatment targets, for future study in canine and human patients. The study of MUO could lead to improvements in the diagnosis, disease subtyping or outcome analysis. The immuno-analyses could provide insights into the aetio-pathogenesis of the disease.