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

doi:10.1007/s00262-016-1841-6

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

Surgery, Surgical Oncology Division

Research output: Contribution to journal › Article › peer-review

21 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 language	English (US)
Pages (from-to)	741-751
Number of pages	11
Journal	Cancer Immunology, Immunotherapy
Volume	65
Issue number	6
DOIs	https://doi.org/10.1007/s00262-016-1841-6
State	Published - Jun 1 2016

Funding

This work was supported by Grant R00CA133244 from the National Cancer Institute (NCI) (to Elizabeth A. Mittendorf), Leukemia SPORE CA100632 (to Jeffrey J. Molldrem), NCI P01 CA148600-01 (to Jeffrey J. Molldrem), Leukemia and Lymphoma Society Research Grant #6030-12 (to Jeffrey J. Molldrem), the T32 CA009599 training grant (to Akhil Chawla and Victor Gall) and the T32 CA009598 training grant (to Celine Kerros and Haley L. Peters) from the NCI. The Flow Cytometry and Cellular Imaging core were supported by Cancer Center Support Grant NCI #CA16672. STR DNA fingerprinting was done by the Cancer Center Support Grant funded Characterized Cell Line core, NCI #CA16672. Elizabeth A. Mittendorf is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center supported by the Jeanne F. Shelby Scholarship Fund. Gheath Alatrash and Elizabeth A. Mittendorf have contributed equally to this work. This work was supported by Grant R00CA133244 from the National Cancer Institute (NCI) (to Elizabeth A. Mittendorf), Leukemia SPORE CA100632 (to Jeffrey J. Molldrem), NCI P01 CA148600-01 (to Jeffrey J. Molldrem), Leukemia and Lymphoma Society Research Grant #6030-12 (to Jeffrey J. Molldrem), the T32 CA009599 training grant (to Akhil Chawla and Victor Gall) and the T32 CA009598 training grant (to Celine Kerros and Haley L. Peters) from the NCI. The Flow Cytometry and Cellular Imaging core were supported by Cancer Center Support Grant NCI #CA16672. STR DNA fingerprinting was done by the Cancer Center Support Grant funded Characterized Cell Line core, NCI #CA16672. Elizabeth A. Mittendorf is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center supported by the Jeanne F. Shelby Scholarship Fund. Gheath Alatrash and Elizabeth A. Mittendorf have contributed equally to this work.

Keywords

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

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00262-016-1841-6

Cite this

Chawla, A., Alatrash, G., Philips, A. V., Qiao, N., Sukhumalchandra, P., Kerros, C., Diaconu, I., Gall, V., Neal, S., Peters, H. L., Clise-Dwyer, K., Molldrem, J. J., & Mittendorf, E. A. (2016). Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells. Cancer Immunology, Immunotherapy, 65(6), 741-751. https://doi.org/10.1007/s00262-016-1841-6

@article{74849320f1334464859e2e7d736936c8,

title = "Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells",

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",

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

note = "Publisher Copyright: {\textcopyright} 2016, Springer-Verlag Berlin Heidelberg.",

year = "2016",

month = jun,

day = "1",

doi = "10.1007/s00262-016-1841-6",

language = "English (US)",

volume = "65",

pages = "741--751",

journal = "Cancer Immunology, Immunotherapy",

issn = "0340-7004",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "6",

}

Chawla, A, Alatrash, G, Philips, AV, Qiao, N, Sukhumalchandra, P, Kerros, C, Diaconu, I, Gall, V, Neal, S, Peters, HL, Clise-Dwyer, K, Molldrem, JJ & Mittendorf, EA 2016, 'Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells', Cancer Immunology, Immunotherapy, vol. 65, no. 6, pp. 741-751. https://doi.org/10.1007/s00262-016-1841-6

TY - JOUR

T1 - Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

AU - Chawla, Akhil

AU - Alatrash, Gheath

AU - Philips, Anne V.

AU - Qiao, Na

AU - Sukhumalchandra, Pariya

AU - Kerros, Celine

AU - Diaconu, Iulia

AU - Gall, Victor

AU - Neal, Samantha

AU - Peters, Haley L.

AU - Clise-Dwyer, Karen

AU - Molldrem, Jeffrey J.

AU - Mittendorf, Elizabeth A.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

KW - Adaptive immunity

KW - Breast cancer

KW - HLA class I

KW - Neutrophil elastase

KW - Tumor-associated neutrophils

UR - http://www.scopus.com/inward/record.url?scp=84964607574&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964607574&partnerID=8YFLogxK

U2 - 10.1007/s00262-016-1841-6

DO - 10.1007/s00262-016-1841-6

M3 - Article

C2 - 27129972

AN - SCOPUS:84964607574

SN - 0340-7004

VL - 65

SP - 741

EP - 751

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

IS - 6

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this