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


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.

SUBMITTER: Arrieta VA 

PROVIDER: S-EPMC8818262 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Arrieta Víctor A VA   Chen Andrew X AX   Kane J Robert JR   Kang Seong Jae SJ   Kassab Cynthia C   Dmello Crismita C   Zhao Junfei J   Burdett Kirsten B KB   Upadhyayula Pavan S PS   Lee-Chang Catalina C   Shilati Joseph J   Jaishankar Dinesh D   Chen Li L   Gould Andrew A   Zhang Daniel D   Yuan Jinzhou J   Zhao Wenting W   Ling Xiaoyang X   Burks Jared K JK   Laffleur Brice B   Amidei Christina C   Bruce Jeffrey N JN   Lukas Rimas V RV   Yamaguchi Jonathan T JT   Cieremans David D   Rothschild Gerson G   Basu Uttiya U   McCord Matthew M   Brat Daniel J DJ   Zhang Hui H   Cooper Lee A D LAD   Zhang Bin B   Sims Peter P   Cloughesy Tim F TF   Prins Robert R   Canoll Peter P   Stupp Roger R   Heimberger Amy B AB   Horbinski Craig C   Iwamoto Fabio M FM   Rabadan Raul R   Sonabend Adam M AM  

Nature cancer 20211129 12


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 o  ...[more]

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