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01-06-2016 | Original Article

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

Authors: 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

Published in: Cancer Immunology, Immunotherapy | Issue 6/2016

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.

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Chawla A, Philips AV, Qiao N, Sukhumalchandra P, Kerros C, Alatrash G, Molldrem JJ, Mittendorf EA (2014) Neutrophil elastase enhances adaptive immunity via increase of peptide presentation and downregulation of T cell inhibitory molecules [Abstract 4843/11] In: Proceedings of the 105th annual meeting of the American Association for Cancer Research, 2014 Apr 5–9, San Diego, CA. Philadelphia (PA): AACR

Title: Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells
Authors: 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
Publication date: 01-06-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 6/2016
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-016-1841-6

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