Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

Akhil Chawla, Gheath Alatrash, Anne V. Philips, Na Qiao, Pariya Sukhumalchandra, Celine Kerros, Iulia Diaconu, Victor Gall, Samantha Neal, Haley L. Peters, Karen Clise-Dwyer, Jeffrey J. Molldrem, Elizabeth A. Mittendorf*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen-processing machinery proteins TAP1, LMP2, and calnexin does not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather, it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV–LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response.

Original languageEnglish (US)
Pages (from-to)741-751
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume65
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

Keywords

  • Adaptive immunity
  • Breast cancer
  • HLA class I
  • Neutrophil elastase
  • Tumor-associated neutrophils

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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