@article{6d0c9a38202744d09a43d0bfdf899a44,
title = "Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma",
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{\textquoteright}s clonal evolution during treatment.",
author = "Junfei Zhao and Chen, {Andrew X.} and Gartrell, {Robyn D.} and Silverman, {Andrew M.} and Luis Aparicio and Tim Chu and Darius Bordbar and David Shan and Jorge Samanamud and Aayushi Mahajan and Ioan Filip and Rose Orenbuch and Morgan Goetz and Yamaguchi, {Jonathan T.} and Michael Cloney and Craig Horbinski and Lukas, {Rimas V.} and Jeffrey Raizer and Rae, {Ali I.} and Jinzhou Yuan and Peter Canoll and Bruce, {Jeffrey N.} and Saenger, {Yvonne M.} and Peter Sims and Iwamoto, {Fabio M.} and Sonabend, {Adam M.} and Raul Rabadan",
note = "Funding Information: This work has been funded by NIH grants R01 CA185486 (R.R.), R01 CA179044 (R.R.), U54 CA193313, U54 209997 (R.R.), R01 NS103473 (P.C., J.N.B., P.S.), NSF/SU2C/V-Foundation Ideas Lab Multidisciplinary Team (PHY-1545805) (R.R.), 2018 Stand Up To Cancer Phillip A. Sharp Innovation in Collaboration Awards (R.R.) and Keep Punching Foundation (F.M.I.). Funding support from Northwestern 5DP5OD021356-04 (A.M. Sonabend), P50CA221747 SPORE for Translational Approaches to Brain Cancer (A.M.Sonabend, R.V.L., C.H.). Developmental funds from The Robert H Lurie NCI Cancer Center Support Grant no. P30CA060553 (A.M. Sonabend). A.X.C. is funded by the Medical Scientist Training Program (T32GM007367). R.D.G. is funded by CUIMC CTSA as TL1 Precision Medicine Fellow (1TL1TR001875-01) and Swim Across America. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = mar,
day = "1",
doi = "10.1038/s41591-019-0349-y",
language = "English (US)",
volume = "25",
pages = "462--469",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",
}