Why glioma brain cancer is often resistant to immunotherapy

Good news! Cancer is history (soon)! But cancer is complex!

"The team analyzed almost 200,000 individual immune cells called myeloid cells from tumor samples from patients with glioma, the most common and aggressive type of primary brain cancer. In a new study in Nature, the researchers found four gene expression “programs” — sets of genes with coordinated activity — that either suppress the immune system or make it more active. They also found that patients treated with dexamethasone, a common treatment for brain cancer patients, showed signs of one of the immunosuppressive programs, suggesting that this drug could reduce the effectiveness of immunotherapy. ...

With this approach, the team identified four programs shaping the immune system.

In two, the immune system was inflammatory; it was activated and potentially trying to attack the tumor.

The other two programs, found in advanced tumors, were immunosuppressive, partially shutting down the immune system and hampering its ability to fight cancer. ...

One of the immunosuppressive programs appeared in patients who had been treated with dexamethasone, a steroid often used to reduce swelling in the brain when a patient first develops symptoms and before they receive immunotherapy. Though scientists knew that dexamethasone is immunosuppressive, they’d previously thought this was primarily due to the medication’s effects on T cells. But the new findings suggest that the drug also strongly impacts myeloid cells, and that dexamethasone should be prescribed more sparingly to improve the efficacy of immunotherapies. ..."

From the abstract:

"Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined.

Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems.

We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours.

The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1β, TGFβ and standard-of-care dexamethasone treatment.

Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies."

Why brain cancer is often resistant to immunotherapy | Broad Institute "Researchers find four coordinated gene expression programs in immune cells from glioma tumors, including two that could lead to immunotherapy resistance."

Programs, origins and immunomodulatory functions of myeloid cells in glioma (open access)

Fig. 1: Identification of consensus superimposable myeloid-cell identity and activity programs.