MHC class I–associated phosphopeptides are the targets of memory-like immunity in Leukemia

Mark Cobbold, Hugo De La Pena, Andrew Norris, Joy M Polefrone, Jie Qian, Ann Michelle English, Kara L Cummings, Sarah Penny, James E Turner, Jennifer Cottine, Jennifer G Abelin, Stacy A Malaker, Angela L Zarling, Hsing-Wen Huang, Oliver Goodyear, Sylvie D Freeman, Jeffrey Shabanowitz, Guy Pratt, Charles Craddock, Michael E WilliamsDonald F Hunt, Victor H Engelhard

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120 Citations (Scopus)
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Abstract

Deregulation of signaling pathways involving phosphorylation is a hallmark of malignant transformation. Degradation of phosphoproteins generates cancer-specific phosphopeptides that are associated with MHC-I and II molecules and recognized by T-cells. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8 T-cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and HLA-matched primary leukemia cells ex vivo. Healthy individuals showed surprisingly high levels of CD8 T-cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients, which correlated with clinical outcome, and was restored following allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T-cell adoptive transfer immunotherapies.
Original languageEnglish
Article number203ra125
JournalScience Translational Medicine
Volume5
Issue number203
DOIs
Publication statusPublished - 18 Sep 2013

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