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

Autor: Víctor A. Arrieta, Bin Zhang, Daniel J. Brat, Xiaoyang Ling, Daniel Zhang, Jinzhou Yuan, David Cieremans, Timothy F. Cloughesy, Lee Cooper, Peter Canoll, Robert M. Prins, Matthew McCord, Roger Stupp, Christina Amidei, Adam M. Sonabend, Gerson Rothschild, Catalina Lee-Chang, Li Chen, Cynthia Kassab, Pavan S. Upadhyayula, Jonathan T. Yamaguchi, Wenting Zhao, Dinesh Jaishankar, Kirsten Bell Burdett, Brice Laffleur, Amy B. Heimberger, Seong Jae Kang, Hui Zhang, Uttiya Basu, Andrew X. Chen, J. Robert Kane, Craig Horbinski, Peter A. Sims, Crismita Dmello, Jared K. Burks, Joseph Shilati, Jeffrey N. Bruce, Fabio M. Iwamoto, Raul Rabadan, Andrew Gould, Rimas V. Lukas, Junfei Zhao
Přispěvatelé: Universidad Nacional Autónoma de México (UNAM), Columbia University [New York], Northwestern University Feinberg School of Medicine, The University of Texas M.D. Anderson Cancer Center [Houston], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, NIHUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USA [1R01NS110703-01A1, 5DP5OD02135605, R01-CA120813, 1R01-CA237418], SPORE for Translational Approaches to Brain Cancer [P50CA221747], Robert H. Lurie Cancer Center Support Grant [P30CA060553], Vagelos Precision Medicine Award [U54CA193313, U54CA209997, R35CA253126], Keep Punching, William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at New York-Presbyterian Hospital, NIAIDUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy and Infectious Diseases (NIAID) [1R01AI099195, R01AI134988], Mexican government through the Mexican National Council for Science and Technology, Plan of Combined Studies in Medicine of the National Autonomous University of Mexico, Medical Scientist Training ProgramUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USA [T32GM007367], Cancer Center Support Grant [NCI CA060553], NIH through MD Andersons Cancer Center Support GrantUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USA [CA016672], NCIUnited States Department of Health and Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R50 CA23707], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California (UC)-University of California (UC)
Rok vydání: 2021
Předmět:
Zdroj: Nature Cancer
Nature Cancer, Nature Research 2021, 2 (12), pp.1372-+. ⟨10.1038/s43018-021-00260-2⟩
Nat Cancer
Nature Cancer, 2021, 2 (12), pp.1372-+. ⟨10.1038/s43018-021-00260-2⟩
ISSN: 2662-1347
DOI: 10.1038/s43018-021-00260-2⟩
Popis: International audience; In two cohorts of patients with glioblastoma who received anti-PD-1, Sonabend and colleagues show that ERK1/2 phosphorylation, detected by immunohistochemistry, provides a biomarker for MAPK/ERK pathway activity and better survival on this therapy. 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.
Databáze: OpenAIRE
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