| Literature DB >> 30742119 |
Junfei Zhao1,2, Andrew X Chen1, Robyn D Gartrell3, Andrew M Silverman3, Luis Aparicio1,2, Tim Chu1,2, Darius Bordbar3, David Shan3, Jorge Samanamud4, Aayushi Mahajan4, Ioan Filip1, Rose Orenbuch1, Morgan Goetz5, Jonathan T Yamaguchi6, Michael Cloney6, Craig Horbinski6,7, Rimas V Lukas8, Jeffrey Raizer8, Ali I Rae9, Jinzhou Yuan2, Peter Canoll10, Jeffrey N Bruce4, Yvonne M Saenger11, Peter Sims2, Fabio M Iwamoto12, Adam M Sonabend13, Raul Rabadan14,15.
Abstract
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.Entities:
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Year: 2019 PMID： 30742119 PMCID： PMC6810613 DOI： 10.1038/s41591-019-0349-y
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440