NEW YORK – Investigators at the Dana-Farber Cancer Institute and elsewhere have identified key mechanisms leading to hypermutation in some glioma tumors, including a hypermutation pathway pushed forward by prior chemotherapy treatment.
As they reported in Nature on Wednesday, the researchers looked at nearly 10,300 glioma tumors that had been molecularly profiled with targeted sequencing panels from the Dana-Farber Cancer Institute (DFCI)-Profile program, Memorial Sloan Kettering Cancer Center, or Foundation Medicine.
While hypermutation is generally rare in newly-diagnosed gliomas, past studies suggest that it is more common in gliomas that recur following chemotherapy. This prompted the researchers to explore the mechanisms leading to hypermutation in some gliomas and the ways that it might impact response to subsequent checkpoint blockade immunotherapy.
Across the 10,294 tumors included in the study, for example, the team detected hypermutation in 2 percent of the newly-diagnosed gliomas and in more than 16 percent of the recurrent tumors. The majority of the hypermutated cases fell in the diffuse glioma subtype and had advanced histology.
Based on mutational signatures and TMB patterns within the subset of hypermutated tumors, the researchers concluded that this phenotype may stem from inherent alterations affecting mismatch repair (MMR) or DNA polymerase genes, or from MMR-related acquired resistance to prior treatment with chemotherapy drugs such as temozolomide.
In their follow-up cell line and single-cell sequencing experiments, the researchers found that they could produce the latter hypermutation signature by treating MMR-deficient glioma cells with temozolomide. They noted that those gliomas tended to show intratumoral heterogeneity, limited infiltration by T immune cells, and relatively low levels of microsatellite instability, along with poor overall survival.
Despite the apparent MMR defects and high TMB in those tumors, the glioma tumors that developed hypermutation phenotypes following temozolomide chemotherapy showed limited response to anti-PD-1 checkpoint blockade immunotherapy, hinting that additional strategies may be needed to boost the immune infiltration in such cases.
"Collectively, these results support a model in which differences in the mutation landscape and antigen clonality of hypermutated gliomas relative to other hypermutated cancers markedly affect the response to immunotherapy and may explain the lack of both recognition of MMR-deficient glioma cells by the host immune system and response to PD-1 blockade, compared to other MMR-deficient cancers," the authors wrote.
The researchers suggested that these and other findings point to the potential benefits of practice changes in the future, writing that "repeated biopsies and sequencing to identify progression and hypermutation could inform prognosis and guide therapeutic management."