Abstract
Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.
Original language | English (US) |
---|---|
Pages (from-to) | 1372-1386 |
Number of pages | 15 |
Journal | Nature Cancer |
Volume | 2 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2021 |
Funding
This work was supported by NIH grant nos. 1R01NS110703-01A1 and 5DP5OD021356-05 (both A.M.S.); no. P50CA221747 SPORE for Translational Approaches to Brain Cancer (principal investigator M. S. Lesniak, with support to A.M.S.); developmental funds from the Robert H. Lurie Cancer Center Support Grant (no. P30CA060553, A.M.S.); Vagelos Precision Medicine Award (F.M.I., R.R. and J.Z.), U54CA193313 (R.R.), U54CA209997 (R.R.), R35CA253126 (R.R.); Keep Punching (F.M.I.); The William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at New York-Presbyterian Hospital (F.M.I.); NIAID nos. 1R01AI099195 (U.B.) and R01AI134988 (U.B.). V.A.A. is financially supported by the Mexican government through the Mexican National Council for Science and Technology and the Plan of Combined Studies in Medicine of the National Autonomous University of Mexico. A.X.C. is funded by the Medical Scientist Training Program (no. T32GM007367). We thank T. Sudhakar for sample collection at Columbia University; K. McCortney, R. Javier and J. Walshon from the Nervous System Tumor Bank supported by the P50CA221747 SPORE for Translational Approaches to Brain Cancer; and B. Shmaltsuyeva for immunohistochemistry at the Northwestern University Pathology Core Facility funded by Cancer Center Support Grant (no. NCI CA060553). We thank L. Kai for technical support on multiplex staining performed at the Immunotherapy Assessment Core at Northwestern University and in the Flow Cytometry & Cellular Imaging Core Facility, which is supported in part by NIH through MD Anderson´s Cancer Center Support Grant no. CA016672, the NCI´s Research Specialist1 (no. R50 CA23707, J.K.B.) and NIH grant nos. R01-CA120813 and 1R01-CA237418 (both A.B.H.).
ASJC Scopus subject areas
- Oncology
- Cancer Research