BIOM-31. ERK1/2 PHOSPHORYLATION PREDICTS SURVIVAL FOLLOWING ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA
| Autor: | Raul Rabadan, Jeffrey N. Bruce, Peter A. Sims, Daniel J. Brat, Matthew R McCord, Pavan S. Upadhyayula, Andrew Gould, Hui Zhang, Gerson Rothschild, Xiaoyang Ling, Kirsten Bell Burdett, Fabio M. Iwamoto, Lee Cooper, Joseph Shilati, Rimas V. Lukas, Junfei Zhao, Cynthia Kassab, Uttiya Basu, Brice Laffleur, Wenting Zhao, Dinesh Jaishankar, Li Chen, Daniel Zhang, Peter Canoll, Robert M. Prins, Amy B. Heimberger, J. Robert Kane, Timothy F. Cloughesy, Catalina Chang, Crismita Dmello, Jared K. Burks, Craig Horbinski, Jinzhou Yuan, David Cieremans, Jonathan T. Yamaguchi, Andrew X. Chen, Roger Stupp, Christina Amidei, Víctor A. Arrieta, Bin Zhang, Adam M. Sonabend, Seong Jae Kang |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Cell cycle checkpoint Extracellular matrix-cell signaling Microglia business.industry medicine.medical_treatment Cancer Immunotherapy medicine.disease medicine.anatomical_structure Oncology medicine Cancer research Phosphorylation Immunohistochemistry Neurology (clinical) Signal transduction business |
| Zdroj: | Neuro-Oncology. 23:vi17-vi17 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noab196.062 |
| Popis: | PD-1 checkpoint inhibition has led to remarkable clinical responses in several cancer types. Whereas PD-1 blockade has not shown an overall survival (OS) benefit for glioblastoma (GBM) patients, a subset of them exhibit long-term responses to this immunotherapy. Previously, we reported an enrichment of BRAF/PTPN11 activating mutations in 30% of recurrent GBMs that responded to PD-1 blockade, but the molecular profile of the majority of responders remained elusive. 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 recurrent GBM, including patients that do not harbor BRAF/PTPN11 mutations. Immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, was performed in a discovery cohort including pre-treatment specimens of 29 recurrent GBM patients treated with adjuvant PD-1 blockade, and 33 patients who did not undergo immunotherapy. p-ERK was predictive of response and OS following PD-1 blockade. Yet p-ERK was not associated with OS in patients not treated with immunotherapy. p-ERK was also associated with OS in a validation GBM cohort treated with adjuvant anti-PD-1 therapy. Single-cell RNA-seq and multiplex-immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and high p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. Thus, our findings indicate that ERK1/2 activation in recurrent GBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype. |
| Databáze: | OpenAIRE |
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