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.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Akhil
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. galatras@mdanderson.org.
authors.forename: Gheath
authors.initials: G
authors.lastname: Alatrash
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anne V
authors.initials: AV
authors.lastname: Philips
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA.
authors.forename: Pariya
authors.initials: P
authors.lastname: Sukhumalchandra
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Kerros
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Gall
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Neal
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA.
authors.forename: Haley L
authors.initials: HL
authors.lastname: Peters
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. eamitten@mdanderson.org.|Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1434, Houston, TX, 77030, USA. eamitten@mdanderson.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism*; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides; D019272:Leukocyte Elastase
keywords: Adaptive immunity; Breast cancer; HLA class I; Neutrophil elastase; Tumor-associated neutrophils