ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma
Victor A. Arrieta
(1)
,
Andrew X. Chen
(2)
,
J. Robert Kane
(3)
,
Seong Jae Kang
(3)
,
Cynthia Kassab
(4)
,
Crismita Dmello
(3)
,
Junfei Zhao
(2)
,
Kirsten B. Burdett
(3)
,
Pavan S. Upadhyayula
(2)
,
Catalina Lee-Chang
(3)
,
Joseph Shilati
(3)
,
Dinesh Jaishankar
(3)
,
Li Chen
(3)
,
Andrew Gould
(3)
,
Daniel Zhang
(3)
,
Jinzhou Yuan
(2)
,
Wenting Zhao
(2)
,
Xiaoyang Ling
(4)
,
Jared K. Burks
(4)
,
Brice Laffleur
(5)
,
Christina Amidei
(3)
,
Jeffrey N. Bruce
(2)
,
Rimas Lukas
(3)
,
Jonathan T. Yamaguchi
(3)
,
David Cieremans
(2)
,
Gerson Rothschild
(2)
,
Uttiya Basu
(2)
,
Matthew Mccord
(3)
,
Daniel J. Brat
(3)
,
Hui Zhang
(3)
,
Lee A. D. Cooper
(3)
,
Bin Zhang
(3)
,
Peter Sims
(2)
,
Tim F. Cloughesy
(6)
,
Robert Prins
(6)
,
Peter Canoll
(2)
,
Roger Stupp
(3)
,
Amy B. Heimberger
(3)
,
Craig Horbinski
(3)
,
Fabio M. Iwamoto
(2)
,
Raul Rabadan
(2)
,
Adam M. Sonabend
(3)
1
UNAM -
Universidad Nacional Autónoma de México = National Autonomous University of Mexico
2 Columbia University [New York]
3 [Northwestern University Medical School] - Feinberg School of Medicine [Northwestern University, Evanston]
4 The University of Texas M.D. Anderson Cancer Center [Houston]
5 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer
6 David Geffen School of Medicine [Los Angeles]
2 Columbia University [New York]
3 [Northwestern University Medical School] - Feinberg School of Medicine [Northwestern University, Evanston]
4 The University of Texas M.D. Anderson Cancer Center [Houston]
5 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer
6 David Geffen School of Medicine [Los Angeles]
Andrew Gould
- Fonction : Auteur
- PersonId : 761307
- ORCID : 0000-0001-9962-9295
Adam M. Sonabend
- Fonction : Auteur correspondant
Résumé
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.