Hypermutations in gliomas: a potential immunotherapy target

Checkpoint inhibitors, like ipilimumab, nivolumab, and pembrolizumab, have provided a breakthrough in cancer immunotherapy, such as in the treatment of melanoma and colorectal and lung cancer. The close relationship between the number of mutations (mutational load) and the response to checkpoint immunotherapy has been convincingly demonstrated in these cancers. Hypermutations in tumors are caused by environmental factors, like UV radiations or cigarette smoking, or by germinal mutations affecting genes of the Mismatch Repair (MMR) machinery, as in the Lynch syndrome. In the context of a high mutational load, a number of neoantigens become visible to the immune system, creating the basis for effective T cell responses. In low- and high-grade gliomas, the most frequent brain tumors, germinal MMR defects are rare; however, hypermutations associated with mutations or decreased expression of MMR genes are rather frequent, occurring in 20-60% of the tumors at recurrence after alkylating chemotherapy with temozolomide. Ongoing clinical trials and genomic investigations will clarify if temozolomide-induced hypermutations, which usually occur in the presence of methylation of the methylguanine methyltransferase gene (MGMT), will be effectively targeted by immunotherapy with checkpoint inhibitors or dendritic cell immunotherapy, thus improving the survival expectations for patients affected by these tumors.