Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma

By Junfei Zhao, Andrew X. Chen, R. Gartrell, A. M. Silverman, Luis C. Aparicio, T. Chu, Darius Bordbar, D. Shan, Jorge L Samanamud, A. Mahajan and 17 more. Nature Medicine, 2019

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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. Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.

Subfields: Genetics, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/4d7a7bd38d1791709eee67d5cea01c55011845df