Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells

Celine Kerros, Satyendra C. Tripathi, Dongxing Zha, Jennifer M. Mehrens, Anna Sergeeva, Anne V. Philips, Na Qiao, Haley L. Peters, Hiroyuki Katayama, Pariya Sukhumalchandra, Kathryn E. Ruisaard, Alexander A. Perakis, Lisa S. St John, Sijie Lu, Elizabeth A. Mittendorf, Karen Clise-Dwyer, Amanda C. Herrmann, Gheath Alatrash, Carlo Toniatti, Samir M. HanashQing Ma, Jeffrey J. Molldrem

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10295-10305
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number24
DOIs
StatePublished - Jun 16 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

MD Anderson CCSG core facilities

  • Monoclonal Antibody Facility
  • Advanced Technology Genomics Core
  • Flow Cytometry and Cellular Imaging Facility
  • Functional Genomics Core
  • Cytogenetics and Cell Authentication Core

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