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Targeting the Leukemia Antigen PR1 with Immunotherapy for the Treatment of Multiple Myeloma.

Alatrash, Gheath; Perakis, Alexander A; Kerros, Celine; Peters, Haley L; Sukhumalchandra, Pariya; Zhang, Mao; Jakher, Haroon; Zope, Madhushree; Patenia, Rebecca; Sergeeva, Anna; Yi, Shuhua; Young, Ken H; Philips, Anne V; Cernosek, Amanda M; Garber, Haven R; Qiao, Na; Weng, Jinsheng; St John, Lisa S; Lu, Sijie; Clise-Dwyer, Karen; Mittendorf, Elizabeth A; Ma, Qing; Molldrem, Jeffrey J.
Clin Cancer Res; 24(14): 3386-3396, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29661776


PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen-presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. As multiple myeloma is derived from B cells, we investigated whether multiple myeloma is also capable of PR1 cross-presentation and subsequently capable of being targeted by using PR1 immunotherapies.


We tested whether multiple myeloma is capable of cross-presenting PR1 and subsequently becomes susceptible to PR1-targeting immunotherapies, using multiple myeloma cell lines, a xenograft mouse model, and primary multiple myeloma patient samples.


Here we show that multiple myeloma cells lack endogenous NE and P3, are able to take up exogenous NE and P3, and cross-present PR1 on HLA-A2. Cross-presentation by multiple myeloma utilizes the conventional antigen processing machinery, including the proteasome and Golgi, and is not affected by immunomodulating drugs (IMiD). Following PR1 cross-presentation, we are able to target multiple myeloma with PR1-CTL and anti-PR1/HLA-A2 antibody both in vitro and in vivoConclusions: Collectively, our data demonstrate that PR1 is a novel tumor-associated antigen target in multiple myeloma and that multiple myeloma is susceptible to immunotherapies that target cross-presented antigens. Clin Cancer Res; 24(14); 3386-96. ©2018 AACR.
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