1. ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma
- Author
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Arrieta, Víctor A, Chen, Andrew X, Kane, J Robert, Kang, Seong Jae, Kassab, Cynthia, Dmello, Crismita, Zhao, Junfei, Burdett, Kirsten B, Upadhyayula, Pavan S, Lee-Chang, Catalina, Shilati, Joseph, Jaishankar, Dinesh, Chen, Li, Gould, Andrew, Zhang, Daniel, Yuan, Jinzhou, Zhao, Wenting, Ling, Xiaoyang, Burks, Jared K, Laffleur, Brice, Amidei, Christina, Bruce, Jeffrey N, Lukas, Rimas V, Yamaguchi, Jonathan T, Cieremans, David, Rothschild, Gerson, Basu, Uttiya, McCord, Matthew, Brat, Daniel J, Zhang, Hui, Cooper, Lee AD, Zhang, Bin, Sims, Peter, Cloughesy, Tim F, Prins, Robert, Canoll, Peter, Stupp, Roger, Heimberger, Amy B, Horbinski, Craig, Iwamoto, Fabio M, Rabadan, Raul, and Sonabend, Adam M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Brain Cancer ,Brain Disorders ,Immunotherapy ,Genetics ,Precision Medicine ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Glioblastoma ,Humans ,MAP Kinase Signaling System ,Neoplasm Recurrence ,Local ,Phosphorylation ,Oncology and carcinogenesis - 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.
- Published
- 2021