Researchers have reprogrammed regulatory T cells in the brain to fight against the most aggressive type of brain cancer – glioblastoma.
Glioblastoma is one of the most aggressive cancers that originates in the brain. Unfortunately, glioblastomas are resistant to immune checkpoint therapies that have revolutionised the treatment of other solid cancers. Clinical benefits have been observed in less than 10% of patients and this is only when the checkpoint inhibitors are used in the neoadjuvant setting. This limited efficacy is mostly due to the highly immunosuppressive tumour microenvironment of glioblastomas.
Glioblastomas are generally considered immunologically ‘cold’. This is because they largely exclude functional cytotoxic CD8 T lymphocytes (CTLs). On the other hand, regulatory T cells (Treg cells) infiltrate the glioblastoma tumour microenvironment. Alongside macrophages they represent the predominant suppressive immune cell populations within glioblastomas that suppress CTL activity. Moreover, glioblastoma tumours tend to have low mutational burden and neoantigen levels. This limits the ability of CTLs to recognise tumour cells.
Reprogramming T cells
In this study, published in Nature Communications, researchers used three preclinical murine models of glioblastoma to show that targeting Treg cells could alter the immunosuppressive tumour microenvironment of glioblastoma. The team achieved this by specifically targeting a receptor on glioblastoma Treg cells known as glucocorticoid-induced TNFR-related receptor (GITR) with an antibody.
The agonistic antibody treatment was able to convert immunosuppressive Treg cells into anti-tumour Th1-like CD4 T cells. They also acquired cytotoxic activity against tumour cells while losing their suppressive function. When combined with an immune checkpoint blocker, anti-programmed cell death 1 antibody (αPD1), this treatment led to a stronger survival benefit in mouse models.
Co-author, Dai Fukumura, commented:
“Importantly, some of these mice not only rejected tumours but developed a long-term immunity against glioblastoma.”
These findings offer a possible solution to overcome resistance to immunotherapy in glioblastoma patients. They also support the use of these antibodies in combination with immune checkpoint blockers, with the current standard-of-care therapies, in patients with high levels of Treg cells to enhance cure rates.
Image credit: By kjpargeter – freepik