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Protein Signatures of NK Cell-Mediated Melanoma Killing Predict Response to Immunotherapies
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 therapeu...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 2021-11, Vol.81 (21), p.5540-5554 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 (
), 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
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
, and proteins involved in mitochondrial metabolism and epithelial-mesenchymal transition were confirmed to regulate
. Two- and three-dimensional killing assays and melanoma xenografts established that the PI
K/AKT/mTOR signaling axis controls
via regulation of NK cell-relevant surface proteins. A "protein-killing-signature" based on the protein analysis predicted
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. |
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ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/0008-5472.CAN-21-0164 |