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 Laffleur; Christina 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

doi:10.1038/s43018-021-00260-2

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

Leukemia

Research output: Contribution to journal › Article › peer-review

37 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 language	English (US)
Pages (from-to)	1372-1386
Number of pages	15
Journal	Nature Cancer
Volume	2
Issue number	12
DOIs	https://doi.org/10.1038/s43018-021-00260-2
State	Published - Dec 2021

ASJC Scopus subject areas

Oncology
Cancer Research
General Medicine

MD Anderson CCSG core facilities

Flow Cytometry and Cellular Imaging Facility

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10.1038/s43018-021-00260-2

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Arrieta, V. A., Chen, A. X., Kane, J. R., Kang, S. J., Kassab, C., Dmello, C., Zhao, J., Burdett, K. B., Upadhyayula, P. S., Lee-Chang, C., Shilati, J., Jaishankar, D., Chen, L., Gould, A., Zhang, D., Yuan, J., Zhao, W., Ling, X., Burks, J. K., ... Sonabend, A. M. (2021). ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma. Nature Cancer, 2(12), 1372-1386. https://doi.org/10.1038/s43018-021-00260-2

Arrieta, VA, Chen, AX, Kane, JR, Kang, SJ, Kassab, C, Dmello, C, Zhao, J, Burdett, KB, Upadhyayula, PS, Lee-Chang, C, Shilati, J, Jaishankar, D, Chen, L, Gould, A, Zhang, D, Yuan, J, Zhao, W, Ling, X, Burks, JK, Laffleur, B, Amidei, C, Bruce, JN, Lukas, RV, Yamaguchi, JT, Cieremans, D, Rothschild, G, Basu, U, McCord, M, Brat, DJ, Zhang, H, Cooper, LAD, Zhang, B, Sims, P, Cloughesy, TF, Prins, R, Canoll, P, Stupp, R, Heimberger, AB, Horbinski, C, Iwamoto, FM, Rabadan, R & Sonabend, AM 2021, 'ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma', Nature Cancer, vol. 2, no. 12, pp. 1372-1386. https://doi.org/10.1038/s43018-021-00260-2

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title = "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.",

author = "Arrieta, {V{\'i}ctor A.} and Chen, {Andrew X.} and Kane, {J. Robert} and Kang, {Seong Jae} and Cynthia Kassab and Crismita Dmello and Junfei Zhao and Burdett, {Kirsten B.} and Upadhyayula, {Pavan S.} and Catalina Lee-Chang and Joseph Shilati and Dinesh Jaishankar and Li Chen and Andrew Gould and Daniel Zhang and Jinzhou Yuan and Wenting Zhao and Xiaoyang Ling and Burks, {Jared K.} and Brice Laffleur and Christina Amidei and Bruce, {Jeffrey N.} and Lukas, {Rimas V.} and Yamaguchi, {Jonathan T.} and David Cieremans and Gerson Rothschild and Uttiya Basu and Matthew McCord and Brat, {Daniel J.} and Hui Zhang and Cooper, {Lee A.D.} and Bin Zhang and Peter Sims and Cloughesy, {Tim F.} and Robert Prins and Peter Canoll and Roger Stupp and Heimberger, {Amy B.} and Craig Horbinski and Iwamoto, {Fabio M.} and Raul Rabadan and Sonabend, {Adam M.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = dec,

doi = "10.1038/s43018-021-00260-2",

language = "English (US)",

volume = "2",

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journal = "Nature Cancer",

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T1 - ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma

AU - Arrieta, Víctor A.

AU - Chen, Andrew X.

AU - Kane, J. Robert

AU - Kang, Seong Jae

AU - Kassab, Cynthia

AU - Dmello, Crismita

AU - Zhao, Junfei

AU - Burdett, Kirsten B.

AU - Upadhyayula, Pavan S.

AU - Lee-Chang, Catalina

AU - Shilati, Joseph

AU - Jaishankar, Dinesh

AU - Chen, Li

AU - Gould, Andrew

AU - Zhang, Daniel

AU - Yuan, Jinzhou

AU - Zhao, Wenting

AU - Ling, Xiaoyang

AU - Burks, Jared K.

AU - Laffleur, Brice

AU - Amidei, Christina

AU - Bruce, Jeffrey N.

AU - Lukas, Rimas V.

AU - Yamaguchi, Jonathan T.

AU - Cieremans, David

AU - Rothschild, Gerson

AU - Basu, Uttiya

AU - McCord, Matthew

AU - Brat, Daniel J.

AU - Zhang, Hui

AU - Cooper, Lee A.D.

AU - Zhang, Bin

AU - Sims, Peter

AU - Cloughesy, Tim F.

AU - Prins, Robert

AU - Canoll, Peter

AU - Stupp, Roger

AU - Heimberger, Amy B.

AU - Horbinski, Craig

AU - Iwamoto, Fabio M.

AU - Rabadan, Raul

AU - Sonabend, Adam M.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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DO - 10.1038/s43018-021-00260-2

M3 - Article

C2 - 35121903

AN - SCOPUS:85115895550

SN - 2662-1347

VL - 2

SP - 1372

EP - 1386

JO - Nature Cancer

JF - Nature Cancer

IS - 12

ER -

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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