TY - JOUR
T1 - Re targeting the leukemia antigen PR1 with immunotherapy for the treatment of multiple myeloma
AU - Alatrash, Gheath
AU - Perakis, Alexander A.
AU - Kerros, Celine
AU - Peters, Haley L.
AU - Sukhumalchandra, Pariya
AU - Zhang, Mao
AU - Jakher, Haroon
AU - Zope, Madhushree
AU - Patenia, Rebecca
AU - Sergeeva, Anna
AU - Yi, Shuhua
AU - Young, Ken H.
AU - Philips, Anne V.
AU - Cernosek, Amanda M.
AU - Garber, Haven R.
AU - Qiao, Na
AU - Weng, Jinsheng
AU - St John, Lisa S.
AU - Lu, Sijie
AU - Clise-Dwyer, Karen
AU - Mittendorf, Elizabeth A.
AU - Ma, Qing
AU - Molldrem, Jeffrey J.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7/15
Y1 - 2018/7/15
N2 - 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 vivo. Conclusions: 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.
AB - 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 vivo. Conclusions: 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.
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U2 - 10.1158/1078-0432.CCR-17-2626
DO - 10.1158/1078-0432.CCR-17-2626
M3 - Article
C2 - 29661776
AN - SCOPUS:85050105423
SN - 1078-0432
VL - 24
SP - 3386
EP - 3396
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -