Targeting the Leukemia Antigen PR1 with Immunotherapy for the Treatment of Multiple Myeloma.
Journal Article (Journal Article)
Purpose: 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.Experimental Design: 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.Results: 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.
- Alatrash, G; Perakis, AA; Kerros, C; Peters, HL; Sukhumalchandra, P; Zhang, M; Jakher, H; Zope, M; Patenia, R; Sergeeva, A; Yi, S; Young, KH; Philips, AV; Cernosek, AM; Garber, HR; Qiao, N; Weng, J; St John, LS; Lu, S; Clise-Dwyer, K; Mittendorf, EA; Ma, Q; Molldrem, JJ
- July 15, 2018
Volume / Issue
- 24 / 14
Start / End Page
- 3386 - 3396
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States