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

Cancer Immunol Immunother. 2016 Jun;65(6):741-51. doi: 10.1007/s00262-016-1841-6. Epub 2016 Apr 29.

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.

Keywords: Adaptive immunity; Breast cancer; HLA class I; Neutrophil elastase; Tumor-associated neutrophils.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigen Presentation / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Gene Expression Regulation*
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Leukocyte Elastase / metabolism*
  • Neoplasms / genetics*
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Peptides / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Peptides
  • Leukocyte Elastase