Recurrent glioblastoma (rGBM) has displayed a varied response to anti-PD-1 immunotherapy, necessitating the identification of predictive biomarkers. Through extensive analyses and 3 clinical studies, we have identified that activation of the MAPK/ERK signaling pathway, particularly ERK1/2 phosphorylation (p-ERK), is associated with longer overall survival (OS) in rGBM patients receiving PD-1 blockade. Initially, enrichment of BRAF/PTPN11 mutations was reported in 30% of responsive rGBM patients, prompting the investigation of p-ERK as a potential marker beyond these mutations.

Our research has unraveled an association between p-ERK abundance and better clinical outcomes following PD-1 blockade, with p-ERK mainly localized in tumor cells. Notably, high p-ERK GBMs contained unique microglia and macrophage phenotypes with elevated MHC class II expression, suggesting a novel interplay between MAPK activation and the tumor immune microenvironment.

While these insights establish a pivotal role for p-ERK in predicting PD-1 blockade response in rGBM, the implementation in clinical settings calls for further validation and accuracy. Nonetheless, these findings pave the way for more personalized and effective immunotherapy strategies, emphasizing the significance of the tumor microenvironment and its interaction with therapeutic interventions in GBM.  

Learning Objectives:

• The activation of the MAPK signaling pathway, specifically ERK1/2 phosphorylation (p-ERK), is identified as a predictive biomarker for longer overall survival in recurrent glioblastoma (eGBM) patients undergoing PD-1 blockade
• High p-ERK tumors in rGBM present a distinct myeloid cell phenotype with elevated MHC class II expression, signifying a connection between MAPK pathway activation and the immune microenvironment
• The implementation of p-ERK as a predictive biomarker in clinical settings requires further validation and exploration of variables impacting its evaluation