Immune Cells are Differentially Shaped by Brain Tumor Microenvironments

Post by Cody Walters

What’s the science?

Brain tumors can result from either mutations to cells endogenous to the central nervous system (primary tumors) or from metastases - cancerous cells arising from tumors elsewhere in the body that infiltrate the brain (secondary tumors). It is unknown whether there are compositional differences between primary and secondary brain tumors. Specifically, it remains unclear whether tumor-associated macrophages play a role in shaping the tumor microenvironment. This week in Cell, Klemm et al. employed a battery of analyses to characterize how the immune landscape is differentially affected in primary and secondary brain cancers.

How did they do it?

The authors analyzed three human brain tissue sample types: non-tumorous, gliomas, and brain metastases. IDH is an enzyme whose mutation status is known to be a close predictor of tumor severity. Thus, brain tumor samples were further divided based on their IDH status: wild type (associated with rapid tumor growth) or mutant (associated with slower tumor growth). The authors investigated various immune cell populations using a variety of methods, namely, flow cytometry (a method for quantifying the size and granularity of single cells) and RNA-seq (a method for measuring which genes in a tissue sample are active and how much those genes have been transcribed). Two tumor-associated macrophage populations — microglia and monocyte-derived macrophages — were of special interest. The authors explored how these two tumor-associated macrophage populations interacted with the tumour microenvironment in gliomas and brain metastases. 

What did they find?

The authors used a panel of cell-surface markers (e.g., CD49D) to differentiate between the two tumour-associated macrophage populations: tumour-associated microglia from tumour-associated monocyte-derived macrophages. They found that tumour-associated microglia and tumour-associated monocyte-derived macrophages expressed different genes based on the tumour type they came from, with principal component analysis revealing that microglia, monocyte-derived macrophages, neutrophils, and T cells explained the most variance in the flow cytometry data. 

The authors investigated the proportion of microglia and monocyte-derived macrophage cells in the different tumour types and found that microglia were relatively more abundant in IDH mutant gliomas whereas monocyte-derived macrophages were relatively more abundant in IDH wild type gliomas. Next, the authors investigated how tissue type (non-tumour, glioma, or brain metastases) influences differential gene expression. Using leading-edge metagene analysis (a method which identifies co-regulated genes across multiple gene sets of interest), they found that microglia and monocyte-derived macrophages coming from different tumour microenvironments have unique transcriptome profiles. This suggests that the microenvironment unique to each type of brain malignancy has the ability to modify the functional state (i.e., the activation state) of tumour-associated macrophages.

The authors then explored whether glioma IDH status (mutant or wild type) modifies tumour-associated macrophage activation state, finding various changes in gene expression associated with IDH status. They were then able to identify relationships between the enrichment of specific gene sets and patient survival rates, showing that tumour-associated- monocyte-derived macrophage IDH wild type gene sets with high enrichments scores were seen in IDH mutant patients with poor survival rates while tumour-associated monocyte-derived macrophage IDH wild type gene sets with low enrichment scores were seen in IDH wild type patients with improved survival rates. Next, they explored whether tumor-infiltrating immune cells affected the tumour microenvironment. In agreement with RNA-seq data, protein array data showed that inflammatory pathways were enriched in brain malignancies. Using self-organizing maps (an unsupervised dimensionality reduction and clustering algorithm) of RNA expression rates, the authors discovered that tumour-associated macrophages contributed significantly to the production of inflammatory proteins (such as SPP1 and IHNBA).

The authors then examined transcriptome changes in tumor-associated macrophages in brain metastases. They found elevated expression of tumour-promoting extracellular matrix proteins in tumour-associated monocyte-derived macrophages relative to tumour-associated microglia, which suggests that tumour-associated monocyte-derived macrophages play a role in remodeling the extracellular matrix and thus sculpting the tumour microenvironment in brain metastases. Finally, the authors looked at T cell activation states in brain metastases, finding that CD4+ T cells were hyperactive while CD8+ T cells were hypoactive (relative to T cells found in IDH wild type gliomas). Furthermore, they found upregulation of T cell activators in tumour-associated macrophage populations (proteins that have either excitatory or inhibitory effects on T cells). These data suggest that tumour-associated macrophages also exert an immunomodulatory effect in brain metastases.

What’s the impact?

Treatment options for brain cancer are limited and the prognosis for patients tends to be poor. Developing an understanding of the tumour microenvironment associated with various brain cancers has the potential to open up a rich pool of candidate targets for new tumour-specific and even genome-specific immunotherapies.

Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells. Cell, (2020). Access the publication here.