Protein Signatures of NK Cell-Mediated Melanoma Killing Predict Response to Immunotherapies.

Autor: Cappello S; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany.; Biophysics, Centre for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany., Sung HM; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany., Ickes C; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany., Gibhardt CS; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany., Vultur A; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany.; The Wistar Institute, Melanoma Research Center, Philadelphia, Pennsylvania., Bhat H; Institute of Immunology, Medical Faculty, University Duisburg-Essen, Essen, Germany., Hu Z; Institute of Immunology, Medical Faculty, University Duisburg-Essen, Essen, Germany., Brafford P; The Wistar Institute, Melanoma Research Center, Philadelphia, Pennsylvania., Denger A; Center for Bioinformatics, Saarland University, Saarbrücken, Germany., Stejerean-Todoran I; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany., Köhn RM; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany., Lorenz V; Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany., Künzel N; Center for Bioinformatics, Saarland University, Saarbrücken, Germany., Salinas G; NGS- Core Unit for Integrative Genomics, Institute for Human Genetics, University Medical Center, Göttingen, Germany., Stanisz H; Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany., Legler T; Department of Transfusion Medicine, University Medical Center Göttingen, Göttingen, Germany., Rehling P; Department of Cellular Biochemistry, University Medical Center, Georg-August-University, Göttingen, Germany.; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany., Schön MP; Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany., Lang KS; Institute of Immunology, Medical Faculty, University Duisburg-Essen, Essen, Germany., Helms V; Center for Bioinformatics, Saarland University, Saarbrücken, Germany., Herlyn M; The Wistar Institute, Melanoma Research Center, Philadelphia, Pennsylvania., Hoth M; Biophysics, Centre for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany., Kummerow C; Biophysics, Centre for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany., Bogeski I; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Center, Georg August University, Göttingen, Germany. ivan.bogeski@med.uni-goettingen.de.; Biophysics, Centre for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany.
Jazyk: angličtina
Zdroj: Cancer research [Cancer Res] 2021 Nov 01; Vol. 81 (21), pp. 5540-5554. Date of Electronic Publication: 2021 Sep 13.
DOI: 10.1158/0008-5472.CAN-21-0164
Abstrakt: Despite impressive advances in melanoma-directed immunotherapies, resistance is common and many patients still succumb to metastatic disease. In this context, harnessing natural killer (NK) cells, which have thus far been sidelined in the development of melanoma immunotherapy, could provide therapeutic benefits for cancer treatment. To identify molecular determinants of NK cell-mediated melanoma killing ( NKmK ), we quantified NK-cell cytotoxicity against a panel of genetically diverse melanoma cell lines and observed highly heterogeneous susceptibility. Melanoma protein microarrays revealed a correlation between NKmK and the abundance and activity of a subset of proteins, including several metabolic factors. Oxidative phoshorylation, measured by oxygen consumption rate, negatively correlated with melanoma cell sensitivity toward NKmK , and proteins involved in mitochondrial metabolism and epithelial-mesenchymal transition were confirmed to regulate NKmK . Two- and three-dimensional killing assays and melanoma xenografts established that the PI 3 K/AKT/mTOR signaling axis controls NKmK via regulation of NK cell-relevant surface proteins. A "protein-killing-signature" based on the protein analysis predicted NKmK of additional melanoma cell lines and the response of patients with melanoma to anti-PD-1 checkpoint therapy. Collectively, these findings identify novel NK cell-related prognostic biomarkers and may contribute to improved and personalized melanoma-directed immunotherapies. SIGNIFICANCE: NK-cell cytotoxicity assays and protein microarrays reveal novel biomarkers of NK cell-mediated melanoma killing and enable development of signatures to predict melanoma patient responsiveness to immunotherapies.
(©2021 American Association for Cancer Research.)
Databáze: MEDLINE
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