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The Role of Antigen Cross-presentation From Leukemia Blasts on Immunity to the Leukemia-associated Antigen PR1

Alatrash, Gheath*; Ono, Yoko; Sergeeva, Anna*; Sukhumalchandra, Pariya*; Zhang, Mao*; St John, Lisa S.*; Yang, Tian-Hui*; Ruisaard, Kathryn*; Armistead, Paul M.; Mittendorf, Elizabeth A.§; He, Hong*; Qiao, Na§; Rodriguez-Cruz, Tania; Liang, Shoudan*; Clise-Dwyer, Karen*; Wieder, Eric D.; Lizee, Gregory; Lu, Sijie*; Molldrem, Jeffrey J.*

Journal of Immunotherapy:
doi: 10.1097/CJI.0b013e31824b3b14
Basic Studies
Abstract

Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.

Author Information

Departments of *Stem Cell Transplantation and Cellular Therapy

§Surgical Oncology

Melanoma, The University of Texas MD Anderson Cancer Center, Houston, TX

Department of Dermatology, University of California Davis, Sacramento, CA

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC

Sylvester Cancer Center, University of Miami, Miami, FL

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.immunotherapy-journal.com.

G.A., Y.O. contributed equally.

Reprints: Jeffrey J. Molldrem, Department of Stem Cell Transplantation and Cellular Therapy, Unit 900, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 (e-mail: jmolldre@mdanderson.org).

Received September 27, 2011

Accepted November 14, 2011

© 2012 Lippincott Williams & Wilkins, Inc.