ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma

Víctor A. Arrieta, Andrew X. Chen, J. Robert Kane, Seong Jae Kang, Cynthia Kassab, Crismita Dmello, Junfei Zhao, Kirsten B. Burdett, Pavan S. Upadhyayula, Catalina Lee-Chang, Joseph Shilati, Dinesh Jaishankar, Li Chen, Andrew Gould, Daniel Zhang, Jinzhou Yuan, Wenting Zhao, Xiaoyang Ling, Jared K. Burks, Brice LaffleurChristina Amidei, Jeffrey N. Bruce, Rimas V. Lukas, Jonathan T. Yamaguchi, David Cieremans, Gerson Rothschild, Uttiya Basu, Matthew McCord, Daniel J. Brat, Hui Zhang, Lee A.D. Cooper, Bin Zhang, Peter Sims, Tim F. Cloughesy, Robert Prins, Peter Canoll, Roger Stupp, Amy B. Heimberger, Craig Horbinski, Fabio M. Iwamoto, Raul Rabadan, Adam M. Sonabend*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 languageEnglish (US)
Pages (from-to)1372-1386
Number of pages15
JournalNature Cancer
Volume2
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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