Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells

Kerros, Celine; Tripathi, Satyendra Chandra; Zha, Dongxing; Mehrens, Jennifer; Сергеева, Анна; Philips, Anne V.; Qiao, Na; Peters, Haley L.; Katayama, Hiroyuki; Sukhumalchandra, Pariya; Ruisaard, Kathryn; Perakis, Alexander A.; John, Lisa S. St.; Lu, Shan; Mittendorf, Elizabeth A.; Clise-Dwyer, Karen; Herrmann, Amanda; Alatrash, Gheath; Toniatti, Carlo; Hanash, Samir M.; Ma, Qing; Molldrem, Jeffrey J.

doi:10.1074/jbc.m116.773051

Cited by 34 publications

(35 citation statements)

References 41 publications

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“…Recent studies have provided evidence that tumor-associated neutrophils can be used as prognostic markers and regulate breast cancer metastasis [ 47 , 48 , 49 ]. Our current data demonstrate that breast cancer cells can influence neutrophils to facilitate cancer progression and metastasis through different complex mechanisms, and these mechanisms can differ between chemotherapy-resistant and parental breast tumor microenvironments.…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Cell–Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities

Saxena

Goel

et al. 2020

Cancers

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Breast cancer remains the most prevalent cancer in women with limited treatment options for patients suffering from therapy-resistance and metastatic disease. Neutrophils play an important role in breast cancer progression and metastasis. We examined the pro-tumorigenic nature of the breast cancer cell–neutrophil interactions and delineated the differences in neutrophil properties between the chemotherapy-resistant and the parent tumor microenvironment. Our data demonstrated that high neutrophil infiltration is associated with disease aggressiveness and therapy resistance. In the human breast cancer dataset, expression of neutrophil-related signature gene expression was higher in tumors from therapy-resistant patients than therapy-sensitive patients. We observed that breast cancer-derived factors significantly enhanced neutrophil survival, polarization, and pro-inflammatory cytokine expression. Breast cancer cell-derived supernatant treated neutrophils significantly expressed high levels of interleukin-1β (IL-1β), CC-chemokine ligand-2-4 (CCL2, CCL3, CCL4), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase-9 (MMP9), and formed extracellular traps (NETs). Moreover, neutrophils showed increased secretion of MMP9 when cultured with the supernatant of chemotherapy-resistant Cl66-Doxorubicin (Cl66-Dox) and Cl66-Paclitaxel (Cl66-Pac) cells in comparison with the supernatant of Cl66-parent cells. Together, these data suggest an important role of breast cancer cell–neutrophil interactions in regulating pro-tumor characteristics in neutrophils and its modulation by therapy resistance.

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Section: Discussionmentioning

confidence: 99%

Breast Cancer Cell–Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities

Saxena

Goel

et al. 2020

Cancers

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“…These data also point to tissue-specificity of CG uptake, since we have shown that breast cancer cells do not take up CG ( 25 ), which could be due to a shared receptor between distinct tumor types that facilitates the uptake of serine proteases ( 43 ). Our results also indicate that the efficiency and rate of CG uptake varies between different cell lines.…”

Section: Discussionmentioning

confidence: 91%

Cathepsin G Is Expressed by Acute Lymphoblastic Leukemia and Is a Potential Immunotherapeutic Target

et al. 2018

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Cathepsin G (CG) is a myeloid azurophil granule protease that is highly expressed by acute myeloid leukemia (AML) blasts and leukemia stem cells. We previously identified CG1 (FLLPTGAEA), a human leukocyte antigen-A2-restricted nonameric peptide derived from CG, as an immunogenic target in AML. In this report, we aimed to assess the level of CG expression in acute lymphoid leukemia (ALL) and its potential as an immunotherapeutic target in ALL. Using RT-PCR and western blots, we identified CG mRNA and protein, respectively, in B-ALL patient samples and cell lines. We also examined CG expression in a large cohort of 130 patients with ALL via reverse-phase protein array (RPPA). Our data show that CG is widely expressed by ALL and is a poor prognosticator. In addition to endogenous expression, we also provide evidence that CG can be taken up by ALL cells. Finally, we demonstrate that patient ALL can be lysed by CG1-specific cytotoxic T lymphocytes in vitro. Together, these data show high expression of CG by ALL and implicate CG as a target for immunotherapy in ALL.

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“…Additionally, this agent has potential therapeutic value as a treatment for solid cancers as well. Previously, we have shown that PR1/HLA-A2 is present on certain solid tumors such as breast cancer, lung cancer, and melanoma (14, 28, 29) via the mechanism of cross-presentation. This further expands a spectrum of diseases that can be treated with the 8F4 bi-specific antibody.…”

Section: Discussionmentioning

confidence: 99%

A Novel T-Cell Engaging Bi-specific Antibody Targeting the Leukemia Antigen PR1/HLA-A2

Herrmann

Pareek

et al. 2019

Front. Immunol.

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Despite substantial advances in the treatment of acute myeloid leukemia (AML), only 30% of patients survive more than 5 years. Therefore, new therapeutics are much needed. Here, we present a novel therapeutic strategy targeting PR1, an HLA-A2 restricted myeloid leukemia antigen. Previously, we have developed and characterized a novel T-cell receptor-like monoclonal antibody (8F4) that targets PR1/HLA-A2 and eliminates AML xenografts by antibody-dependent cellular cytotoxicity (ADCC). To improve the potency of 8F4, we adopted a strategy to link T-cell cytotoxicity with a bi-specific T-cell-engaging antibody that binds PR1/HLA-A2 on leukemia and CD3 on neighboring T-cells. The 8F4 bi-specific antibody maintained high affinity and specific binding to PR1/HLA-A2 comparable to parent 8F4 antibody, shown by flow cytometry and Bio-Layer Interferometry. In addition, 8F4 bi-specific antibody activated donor T-cells in the presence of HLA-A2+ primary AML blasts and cell lines in a dose dependent manner. Importantly, activated T-cells lysed HLA-A2+ primary AML blasts and cell lines after addition of 8F4 bi-specific antibody. In conclusion, our studies demonstrate the therapeutic potential of a novel bi-specific antibody targeting the PR1/HLA-A2 leukemia-associated antigen, justifying further clinical development of this strategy.

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Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells

Cited by 34 publications

References 41 publications

Breast Cancer Cell–Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities

Breast Cancer Cell–Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities

Cathepsin G Is Expressed by Acute Lymphoblastic Leukemia and Is a Potential Immunotherapeutic Target

A Novel T-Cell Engaging Bi-specific Antibody Targeting the Leukemia Antigen PR1/HLA-A2

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