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      B-Helper Neutrophils in Regional Lymph Nodes Correlate with Improved Prognosis in Patients with Head and Neck Cancer

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          Abstract

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          Neutrophils exhibit multiple functions during cancer progression and are believed to regulate adaptive immune responses to cancer. In addition to their interactions with T cells in this context, these cells are also believed to interact with B cells. Neutrophils have been found in the marginal zone of the spleen, where they exhibit helper cell characteristics, supporting B cell proliferation and activation. Here, we investigate the effect of neutrophils on B cells in the regional lymph nodes (RLN) of head-and-neck cancer (HNC) patients. We have identified that, in RLNs, neutrophils express a helper cell phenotype that was associated with the increased activation and proliferation of B cells. Importantly, the high abundance of neutrophils in the B cell follicles of regional lymph nodes is associated with significantly improved HNC patient survival.

          Abstract

          The role of neutrophils during cancer formation and elimination is diverse. Here, for the first time, we investigate neutrophil helper cells (N BH), their influence on B cell activity in the regional lymph nodes (RLN) of head-and-neck cancer patients and the effect of this neutrophil/B cell interaction on patient prognosis. Circulating and RLN neutrophils of patients with stage I–IV head-and-neck squamous cell carcinoma were investigated with flow cytometry and qPCR. In addition, neutrophil/B cell co-localization in RLNs was evaluated using immunohistochemistry. B cell proliferation was assessed and correlated with the distance to neutrophils. Patient survival was evaluated. Neutrophils with the helper cell phenotype were identified in the RLN of HNC patients. B cells in close proximity to such N BH showed significantly higher proliferation rates, together with elevated activation-induced cytidine deaminase (AID) expression. Notably, patient survival was significantly higher in individuals with high N BH frequencies in the B follicles of RLNs. Neutrophils in RLN can support T cell-independent activation of the adaptive immune system through B cell stimulation, capturing helper cell phenotype character. The presence of such helper neutrophils in the RLNs of HNC patients positively correlates with patient prognosis.

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          Most cited references39

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          Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.

          TGF-beta blockade significantly slows tumor growth through many mechanisms, including activation of CD8(+) T cells and macrophages. Here, we show that TGF-beta blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b(+)/Ly6G(+) tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-beta blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8(+) T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8(+) T cells intratumorally. Together, these data suggest that TGF-beta within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-beta blockade results in the recruitment and activation of TANs with an antitumor phenotype.
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            Tertiary lymphoid structures in the era of cancer immunotherapy

            Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.
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              Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer

              Evidence indicates that lung cancer development is a complex process that involves interactions between tumor cells, stromal fibroblasts, and immune cells. Tumor-infiltrating immune cells play a significant role in the promotion or inhibition of tumor growth. As an integral component of the tumor microenvironment, tumor-infiltrating B lymphocytes (TIBs) exist in all stages of cancer and play important roles in shaping tumor development. Here, we review recent clinical and preclinical studies that outline the role of TIBs in lung cancer development, assess their prognostic significance, and explore the potential benefit of B cell-based immunotherapy for lung cancer treatment.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                21 June 2021
                June 2021
                : 13
                : 12
                Affiliations
                [1 ]Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany; Ekaterina.Pylaeva@ 123456uk-essen.de (E.P.); irem.oezel@ 123456uk-essen.de (I.O.); ilona.spyra@ 123456uk-essen.de (I.S.); charlotte.wallner@ 123456gmx.de (C.W.); magda.korek@ 123456gmail.com (M.K.); georg.korschunow@ 123456gmx.ch (G.K.); maksim.domnich@ 123456uk-essen.de (M.D.); elena.siakaeva@ 123456uk-essen.de (E.S.); stephan.lang@ 123456uk-essen.de (S.L.)
                [2 ]Institute of Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45141 Essen, Germany; anthony.squire@ 123456uk-essen.de
                [3 ]Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; Moritz.Goetz@ 123456uk-essen.de (M.G.); agnes.bankfalvi@ 123456uk-essen.de (A.B.)
                [4 ]German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, 45147 Essen, Germany
                Author notes
                [†]

                These authors contributed equally.

                [‡]

                These authors contributed equally.

                Article
                cancers-13-03092
                10.3390/cancers13123092
                8234083
                003dc846-58b4-4a6a-844e-298f81550cba
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                neutrophils,b cells,b helper neutrophils,nbh,head-and-neck cancer,lymph nodes,regional lymph nodes,head-and-neck squamous cell carcinoma

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