TY - JOUR
T1 - Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells
AU - Kerros, Celine
AU - Tripathi, Satyendra C.
AU - Zha, Dongxing
AU - Mehrens, Jennifer M.
AU - Sergeeva, Anna
AU - Philips, Anne V.
AU - Qiao, Na
AU - Peters, Haley L.
AU - Katayama, Hiroyuki
AU - Sukhumalchandra, Pariya
AU - Ruisaard, Kathryn E.
AU - Perakis, Alexander A.
AU - St John, Lisa S.
AU - Lu, Sijie
AU - Mittendorf, Elizabeth A.
AU - Clise-Dwyer, Karen
AU - Herrmann, Amanda C.
AU - Alatrash, Gheath
AU - Toniatti, Carlo
AU - Hanash, Samir M.
AU - Ma, Qing
AU - Molldrem, Jeffrey J.
N1 - Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/6/16
Y1 - 2017/6/16
N2 - Neutrophil elastase (NE) can be rapidly taken up by tumor cells that lack endogenous NE expression, including breast cancer, which results in cross-presentation of PR1, an NE-derived HLA-A2-restricted peptide that is an immunotherapy target in hematological and solid tumor malignancies. The mechanism of NE uptake, however, remains unknown. Using the mass spectrometry-based approach, we identify neuropilin-1 (NRP1) as a NE receptor that mediates uptake and PR1 cross-presentation in breast cancer cells. We demonstrated that soluble NE is a specific, high-affinity ligand for NRP1 with a calculated Kd of 38.7 nM. Furthermore, we showed that NRP1 binds to the RRXR motif in NE. Notably, NRP1 knockdown with interfering RNA or CRISPR-cas9 system and blocking using anti-NRP1 antibody decreased NE uptake and, subsequently, susceptibility to lysis by PR1-specific cytotoxic T cells. Expression of NRP1 in NRP1-deficient cells was sufficient to induce NE uptake. Altogether, because NRP1 is broadly expressed in tumors, our findings suggest a role for this receptor in immunotherapy strategies that target cross-presented antigens.
AB - Neutrophil elastase (NE) can be rapidly taken up by tumor cells that lack endogenous NE expression, including breast cancer, which results in cross-presentation of PR1, an NE-derived HLA-A2-restricted peptide that is an immunotherapy target in hematological and solid tumor malignancies. The mechanism of NE uptake, however, remains unknown. Using the mass spectrometry-based approach, we identify neuropilin-1 (NRP1) as a NE receptor that mediates uptake and PR1 cross-presentation in breast cancer cells. We demonstrated that soluble NE is a specific, high-affinity ligand for NRP1 with a calculated Kd of 38.7 nM. Furthermore, we showed that NRP1 binds to the RRXR motif in NE. Notably, NRP1 knockdown with interfering RNA or CRISPR-cas9 system and blocking using anti-NRP1 antibody decreased NE uptake and, subsequently, susceptibility to lysis by PR1-specific cytotoxic T cells. Expression of NRP1 in NRP1-deficient cells was sufficient to induce NE uptake. Altogether, because NRP1 is broadly expressed in tumors, our findings suggest a role for this receptor in immunotherapy strategies that target cross-presented antigens.
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U2 - 10.1074/jbc.M116.773051
DO - 10.1074/jbc.M116.773051
M3 - Article
C2 - 28468826
AN - SCOPUS:85020877299
SN - 0021-9258
VL - 292
SP - 10295
EP - 10305
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 24
ER -