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Researchers at Northwestern have identified a biological pathway that may help explain why some glioblastoma (GBM) patients respond to immunotherapy while many do not. Using CRISPR-based screening in mouse models, they found that activation of the MAPK/RAF-MEK-ERK signaling pathway made tumors more recognizable to the immune system and improved responses to immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 therapies.
The findings build on earlier observations that rare BRAF and PTPN11 mutations, which activate MAPK signaling, were more common among the small number of GBM patients who had exceptional responses to immunotherapy. The researchers found that MAPK/ERK activation increases inflammatory signals, promotes T-cell infiltration into tumors, and may help immune cells recognize and attack cancer cells.
The team cautions that MAPK activation is necessary but not sufficient for immunotherapy response; in other words, some patients with this pathway activation still do not respond. If validated in human studies, MAPK/ERK activity could become a biomarker to help identify which GBM patients are most likely to benefit from immunotherapies.