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

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

doi:10.1007/s00262-016-1841-6

Cited by 20 publications

(13 citation statements)

References 43 publications

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“…Mature DCs were generated from monocytes isolated through a previously described adherence culturing methodology (23). Briefly, Buffy coats from healthy human donors were obtained from the MD Anderson Cancer Center Blood Bank.…”

Section: Methodsmentioning

confidence: 99%

Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells

et al. 2017

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Early phase clinical trials evaluating CD8+ T cell-eliciting, HER2-derived peptide vaccines administered to HER2-positive breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the monoclonal antibody targeting the HER2 protein. Among 60 patients enrolled on clinical trials evaluating the E75+GM-CSF and GP2+GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein; an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. Based on these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy.

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Section: Methodsmentioning

confidence: 99%

Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells

et al. 2017

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“…By contrast, NE could also restrain antitumor immune response. In fact, NE taken up by breast cancer cells upregulated the expression of HLA class I in tumor cells, thus increasing the responsiveness of breast cancer cells to adaptive immunity . Moreover, once taken up by breast cancer cells, NE cleaved cyclin E, which was then presented in a truncated form in HLA‐I context and efficiently activated a CTL‐mediated antitumor response .…”

Section: Introductionmentioning

confidence: 99%

Roles of neutrophils in cancer growth and progression

Galdiero

Varricchi

Loffredo

et al. 2017

Journal of Leukocyte Biology

130

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Chronic inflammation is a well-known tumor-enabling capacity, which allows nascent tumors to acquire all the hallmark capabilities, including the escape from immunosurveillance. Soluble and cellular inflammatory mediators constitute the complex network of the tumor microenvironment, in which tumors grow and with which constantly interact. Myeloid cells (e.g., tumor associated macrophages) are pivotal players of the tumor microenvironment and are characterized by plasticity, which consists of the ability to acquire distinct phenotypes in response to the microenvironment in which they reside. Neutrophils are emerging as important players of tumor microenvironment, given their heterogeneity and plasticity. Increasing evidence suggests a dual role for neutrophils in modulating tumor behavior and highlights the need for a reassessment of neutrophil functions in cancer initiation and progression.

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“…Mutations near Asn88 and Asn124 altered the N-glycan processing, secretion and the proteolytic activity of HNE, but the N-glycosylation structure and function relationship of HNE was not investigated. In fact, given the importance of HNE in mediating a functional host immune response (33,34), and the increasing appreciation that protein N-glycosylation significantly modulates the function of proteins (35,36), the structure/function relationship of the N-glycosylation of this vital serine protease remains understudied.…”

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confidence: 99%

Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions*.

Loke

Østergaard

Heegaard

et al. 2017

Molecular & Cellular Proteomics

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Human neutrophil elastase (HNE) is an important -glycosylated serine protease in the innate immune system, but the structure and immune-modulating functions of HNE-glycosylation remain undescribed. Herein, LC-MS/MS-based glycan, glycopeptide and glycoprotein profiling were utilized to first determine the heterogeneous -glycosylation of HNE purified from neutrophil lysates and then from isolated neutrophil granules of healthy individuals. The spatiotemporal expression of HNE during neutrophil activation and the biological importance of its-glycosylation were also investigated using immunoblotting, cell surface capture, native MS, receptor interaction, protease inhibition, and bacteria growth assays. Site-specific HNE glycoprofiling demonstrated that unusual paucimannosidic -glycans, particularly Manα1,6Manβ1,4GlcNAcβ1,4(Fucα1,6)GlcNAcβ, predominantly occupied Asn124 and Asn173. The equally unusual core fucosylated monoantenna complex-type-sialoglycans also decorated these two fully occupied sites. In contrast, the mostly unoccupied Asn88 carried nonfucosylated paucimannosidic -glycans probably resulting from low glycosylation site solvent accessibility. Asn185 was not glycosylated. Subcellular- and site-specific glycoprofiling showed highly uniform-glycosylation of HNE residing in distinct neutrophil compartments. Stimulation-induced cell surface mobilization demonstrated a spatiotemporal regulation, but not cell surface-specific glycosylation signatures, of HNE in activated human neutrophils. The three glycosylation sites of HNE were located distal to the active site indicating glycan functions other than interference with HNE enzyme activity. Functionally, the paucimannosidic HNE glycoforms displayed preferential binding to human mannose binding lectin compared with the HNE sialoglycoforms, suggesting a glycoform-dependent involvement of HNE in complement activation. The heavily -glycosylated HNE protease inhibitor, α1-antitrypsin, displayed concentration-dependent complex formation and preferred glycoform-glycoform interactions with HNE. Finally, both enzymatically active HNE and isolated HNE-glycans demonstrated low micromolar concentration-dependent growth inhibition of clinically-relevant , suggesting some bacteriostatic activity is conferred by the HNE-glycans. Taken together, these observations support that the unusual HNE -glycosylation, here reported for the first time, is involved in modulating multiple immune functions central to inflammation and infection.

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

Cited by 20 publications

References 43 publications

Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells

Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells

Roles of neutrophils in cancer growth and progression

Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions*.

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