Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma
Menée à partir de données portant sur 66 patients atteints d'un glioblastome traité par témozolomide et radiothérapie puis par pembrolizumab ou nivolumab après récidive de la maladie, cette étude analyse la corrélation entre l'évolution du profil génomique de la tumeur et de son micro-environnement immunitaire durant le traitement et l'efficacité des anti-PD-1
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.