Friederike Hoffmann1, Romina Zarbl2, Dennis Niebel1, Judith Sirokay1, Anne Fröhlich1, Christian Posch3,4, Tobias A W Holderried5, Peter Brossart5, Gonzalo Saavedra1, Pia Kuster1, Sebastian Strieth2, Gerrit H Gielen6, Sandra S Ring7,8, Jörn Dietrich2, Torsten Pietsch6, Lukas Flatz8,9,10,11, Glen Kristiansen12, Jennifer Landsberg1, Dimo Dietrich13. 1. Department of Dermatology and Allergology, University Hospital Bonn, Bonn, Germany. 2. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. 3. Department of Dermatology and Allergology, Technical University of Munich, Munich, Germany. 4. Faculty of Medicine, Sigmund Freud University, Vienna, Austria. 5. Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany. 6. Institute of Neuropathology, University Hospital Bonn, Bonn, Germany. 7. Microbiology and Immunology PhD Program, University of Zurich, Zurich, Switzerland. 8. Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland. 9. Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland. 10. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. 11. Department of Dermatology and Allergology, Kantonsspital St Gallen, St Gallen, Switzerland. 12. Institute of Pathology, University Hospital Bonn, Bonn, Germany. 13. Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. dimo.dietrich@gmail.com.
Abstract
BACKGROUND: PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma. METHODS: DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression. RESULTS: We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival. CONCLUSION: PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.
BACKGROUND:PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma. METHODS: DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in humanmelanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanomapatients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanomapatients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression. RESULTS: We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival. CONCLUSION:PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanomapatients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.
Authors: Agnieszka Karczmarczyk; Maciej Korpysz; Sylwia Bilska; Joanna Purkot; Marek Hus; Krzysztof Giannopoulos Journal: Cancer Manag Res Date: 2022-03-28 Impact factor: 3.989
Authors: Dennis Niebel; Anne Fröhlich; Jennifer Landsberg; Dimo Dietrich; Romina Zarbl; Simon Fietz; Luka de Vos; Timo J Vogt; Jörn Dietrich; Judith Sirokay; Pia Kuster; Gonzalo Saavedra; Susana Ramírez Valladolid; Friederike Hoffmann; Sebastian Strieth Journal: Clin Epigenetics Date: 2022-04-11 Impact factor: 6.551
Authors: Juan Luis Onieva; Qingyang Xiao; Miguel-Ángel Berciano-Guerrero; Aurora Laborda-Illanes; Carlos de Andrea; Patricia Chaves; Pilar Piñeiro; Alicia Garrido-Aranda; Elena Gallego; Belén Sojo; Laura Gálvez; Rosario Chica-Parrado; Daniel Prieto; Elisabeth Pérez-Ruiz; Angela Farngren; María José Lozano; Martina Álvarez; Pedro Jiménez; Alfonso Sánchez-Muñoz; Javier Oliver; Manuel Cobo; Emilio Alba; Isabel Barragán Journal: Int J Mol Sci Date: 2022-08-15 Impact factor: 6.208