MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia.
Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. 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 human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust 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. This reduction correlated with clinical outcome; however, immunity was restored after 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.
Carter Immunology Center and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
Mark
M
Cobbold
Hugo
H
De La Peña
Andrew
A
Norris
Joy M
JM
Polefrone
Jie
J
Qian
Ann Michelle
AM
English
Kara L
KL
Cummings
Sarah
S
Penny
James E
JE
Turner
Jennifer
J
Cottine
Jennifer G
JG
Abelin
Stacy A
SA
Malaker
Angela L
AL
Zarling
Hsing-Wen
HW
Huang
Oliver
O
Goodyear
Sylvie D
SD
Freeman
Jeffrey
J
Shabanowitz
Guy
G
Pratt
Charles
C
Craddock
Michael E
ME
Williams
Donald F
DF
Hunt
Victor H
VH
Engelhard
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007938:Leukemia / Q000276:immunology*; D008285:Major Histocompatibility Complex; D010748:Phosphopeptides / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D010748:Phosphopeptides