Spatial analysis of canine glioma reveals heterogeneous intratumoral niches characterized by distinct patterns of cell plasticity and immunosuppression

Gliomas, a lethal type of brain cancer, currently have few treatment options. Immune checkpoint inhibitors (ICI) have shown promise as a new method of treatment for human gliomas (HG), but clinical trials have produced inconsistent results. The major obstacle to using ICI for cancer is a process called epithelial-mesenchymal plasticity (EMP), which drives immunosuppression within tumors.

However, studying EMP in cancer cells and immune cells in a lab setting or using mouse models is difficult, as these models do not accurately reflect the interactions between cancer cells and immune cells. Formalin-fixed, paraffin-embedded (FFPE) patient-derived canine glioma (CG) samples, on the other hand, present an attractive alternative.

Although researchers cannot manipulate these tissues, CG tissue is notoriously immunologically "cold" and is being studied as a model for human gliomas (HG). Additionally, the immune microenvironment in CG develops in a way that is similar to what humans experience in real life. However, it is still unclear if CGs contain heterogeneous regions where different types of cells with varying plasticity and immunosuppressive properties are found.

Understanding the immune landscape of CG in relation to EMP is therefore crucial for determining whether CGs can be used as a model for predicting responses to immunotherapy in human gliomas (HG). By combining traditional histology, immunohistochemistry, and spatial transcriptomics, researchers analyzed 30 low-grade (LGr) and high-grade (HGr) FFPE CG cases (10 cases each of LGr and HGr).

All subtypes of CG were found to have heterogeneous immunosuppressive regions associated with different EMP phenotypes. Astrocytomas, for example, showed a more mesenchymal identity and recruited a specific type of immune cell called tumor-associated macrophages (TAMs). Oligodendrogliomas displayed a strong stem-like signature and had an unusual combination of genes (FOXP3/LAG3/SNAI1) that were located right at the intersection of immunosuppression and EMP.

Across all subtypes of CG, a more mesenchymal phenotype was often found alongside TAMs, and there was evidence of dysfunction and exhaustion in the immune cells within the tumor. In conclusion, the study shows that CFs closely resemble the heterogeneous mix of EMP and immunosuppression seen in human gliomas. More importantly, the findings highlight the importance of subtyping gliomas, as different subtypes have distinct ways of undergoing EMP and evading the immune system, which is crucial for translating findings into real-world treatments.