Although brain tumors have largely remained resistant to immunotherapy, a new study has shown that a slow-growing brain tumor arising in patients affected by neurofibromatosis type 1 (NF1) may be vulnerable to that treatment approach. The findings (“The molecular landscape of glioma in patients with Neurofibromatosis 1”), made by an international consortium led by researchers at Columbia University Vagelos College of Physicians and Surgeons, were published online in Nature Medicine.
An estimated 100,000 individuals in the United States have NF1, a hereditary disease that can lead to the development of tumors throughout the nervous system, including a type of brain tumor called a glioma. Children usually have a slow-growing type of glioma, whereas adults often have a more aggressive type.
But whether slow-growing or not, gliomas are difficult to treat. Most are highly resistant to chemotherapy, and radiotherapy can aggravate, rather than relieve, symptoms, such as headaches and seizures. Since the tumors typically engulf delicate brain regions, surgery is rarely an option.
Surprisingly little was known about the molecular changes that occur in NF1 brain tumors, which has made it difficult to develop targeted therapies. In this study, researchers from 25 institutions around the world, led by Columbia’s Antonio Iavarone, M.D., and Anna Lasorella, M.D., performed an in-depth analysis of tumor samples from 56 patients to create the first comprehensive inventory of the genetic, epigenetic, and immune alterations in NF1 gliomas.
“NF1 is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma),” wrote the investigators.
“We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with alternative lengthening of telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.”
“This inventory will give us a much better idea of how to design individualized treatments,” Dr. Iavarone said, “but two findings from our study may have immediate clinical repercussions for NF1 patients.”
Immunotherapy is ineffective for most brain tumors because the tumors are infiltrated with large numbers of macrophages that thwart the immune system’s attack. The new study revealed that many slow-growing NF1 gliomas contain few macrophages and produce neoantigens that can trigger an immune system attack.
“We were surprised to find that approximately 50% of the slow-growing NF1 gliomas contained large numbers of T cells that have the ability to destroy cancer cells,” said Dr. Lasorella. These high immune tumors are good candidates for treatment with immunotherapy, which could unleash the T cells, and clinical trials are now being planned.
This study also discovered that a subgroup of brain tumors in patients without NF1 share the same molecular profile as the slow-growing NF1 gliomas. Future studies will have to establish whether these NF1-glioma-like brain tumors also exhibit the same immune features and are potentially vulnerable to immunotherapy.
Although aggressive NF1 tumors were packed with macrophages and are likely to resist immunotherapy, the researchers also found that many had a genetic defect that may leave them more sensitive to DNA-damaging therapies. Cells in these aggressive tumors can reproduce, but the new cells contain many DNA errors.
“If we treat the aggressive tumors with DNA-damaging agents, we might be able to introduce even more DNA errors that eventually prevent the cells from replicating and stall the growth of the tumor,” said Dr. Iavarone.
Radiotherapy and some current cancer drugs damage DNA, but drugs are also in development that may be more effective in cancer cells with this specific genetic defect.
