Publications by authors named "William Vermi"

137 Publications

CD66bCD64CD115 cells in the human bone marrow represent neutrophil-committed progenitors.

Nat Immunol 2022 May 28;23(5):679-691. Epub 2022 Apr 28.

Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy.

Here we report the identification of human CD66bCD64CD115 neutrophil-committed progenitor cells (NCPs) within the SSCCD45CD34 and CD34 subsets in the bone marrow. NCPs were either CD45RA or CD45RA, and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments. Single-cell RNA-sequencing analysis indicated NCPs fell into four clusters, characterized by different maturation stages and distributed along two differentiation routes. One of the clusters was characterized by an interferon-stimulated gene signature, consistent with the reported expansion of peripheral mature neutrophil subsets that express interferon-stimulated genes in diseased individuals. Finally, comparison of transcriptomic and phenotypic profiles indicated NCPs represented earlier neutrophil precursors than the previously described early neutrophil progenitors (eNePs), proNeus and COVID-19 proNeus. Altogether, our data shed light on the very early phases of neutrophil ontogeny.
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http://dx.doi.org/10.1038/s41590-022-01189-zDOI Listing
May 2022

Tissue-resident FOLR2 macrophages associate with CD8 T cell infiltration in human breast cancer.

Cell 2022 Mar 23;185(7):1189-1207.e25. Epub 2022 Mar 23.

Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK.

Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2 tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2 macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8 T cells. FOLR2 macrophages efficiently prime effector CD8 T cells ex vivo. The density of FOLR2 macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
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http://dx.doi.org/10.1016/j.cell.2022.02.021DOI Listing
March 2022

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer.

Cancers (Basel) 2022 Jan 11;14(2). Epub 2022 Jan 11.

Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.

Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways.
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http://dx.doi.org/10.3390/cancers14020348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773716PMC
January 2022

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms.

Cancers (Basel) 2021 Nov 12;13(22). Epub 2021 Nov 12.

Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.

Several studies have reported that cellular and soluble components of the tumor microenvironment (TME) play a key role in cancer-initiation and progression. Considering the relevance and the complexity of TME in cancer biology, recent research has focused on the investigation of the TME content, in terms of players and informational exchange. Understanding the crosstalk between tumor and non-tumor cells is crucial to design more beneficial anti-cancer therapeutic strategies. Malignant pleural mesothelioma (MPM) is a complex and heterogenous tumor mainly caused by asbestos exposure with few treatment options and low life expectancy after standard therapy. MPM leukocyte infiltration is rich in macrophages. Given the failure of macrophages to eliminate asbestos fibers, these immune cells accumulate in pleural cavity leading to the establishment of a unique inflammatory environment and to the malignant transformation of mesothelial cells. In this inflammatory landscape, stromal and immune cells play a driven role to support tumor development and progression via a bidirectional communication with tumor cells. Characterization of the MPM microenvironment (MPM-ME) may be useful to understand the complexity of mesothelioma biology, such as to identify new molecular druggable targets, with the aim to improve the outcome of the disease. In this review, we summarize the known evidence about the MPM-ME network, including its prognostic and therapeutic relevance.
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http://dx.doi.org/10.3390/cancers13225664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616064PMC
November 2021

Tumor Cells and the Extracellular Matrix Dictate the Pro-Tumoral Profile of Macrophages in CRC.

Cancers (Basel) 2021 Oct 16;13(20). Epub 2021 Oct 16.

Department of Biology, University of Padova, 35131 Padova, Italy.

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. In colorectal cancer (CRC), a strong infiltration of TAMs is accompanied by a decrease in effector T cells and an increase in the metastatic potential of CRC. We investigated the functional profile of TAMs infiltrating CRC tissue by immunohistochemistry, flow cytometry, ELISA, and qRT-PCR and their involvement in impairing the activation of effector T cells. In CRC biopsies, we evidenced a high percentage of macrophages with low expression of the antigen-presenting complex MHC-II and high expression of CD206. Monocytes co-cultured with tumor cells or a decellularized tumor matrix differentiated toward a pro-tumoral macrophage phenotype characterized by decreased expression of MHC-II and CD86 and increased expression of CD206 and an abundant release of pro-tumoral cytokines and chemokines. We demonstrated that the hampered expression of MHC-II in macrophages is due to the downregulation of the MHC-II transactivator CIITA and that this effect relies on increased expression of miRNAs targeting CIITA. As a result, macrophages become unable to present antigens to CD4 T lymphocytes. Our data suggest that the tumor microenvironment contributes to defining a pro-tumoral profile of macrophages infiltrating CRC tissue with impaired capacity to activate T cell effector functions.
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http://dx.doi.org/10.3390/cancers13205199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533926PMC
October 2021

Metavariables Resuming Host Immune Features and Nodal Involvement Are Associated with Oncological Outcomes in Oral Cavity Squamous Cell Carcinoma.

Cells 2021 08 26;10(9). Epub 2021 Aug 26.

Department of Molecular and Translational Medicine, University of Brescia, 25125 Brescia, Italy.

Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8 T-cells. To this end, CD8 T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODAL) and primary tumor (TUMOR) involvement, the frequency of myeloid (MYELOID) or lymphoid (LYMPHOID) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8 T-cells (TI-CD8). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODAL was significantly associated with all tested outcomes ( < 0.001), the LYMPHOID showed a significant association with the overall, disease-specific and distant recurrence-free survival ( < 0.05) and the MYELOID with the locoregional control only ( < 0.001). Finally, TI-CD8 was associated with distant recurrence-free survival ( = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODAL and immune metavariables (LYMPHOID, MYELOID and TI-CD8) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.
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http://dx.doi.org/10.3390/cells10092203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472482PMC
August 2021

Adalimumab for interleukin-1β-mediated chronic non-scarring scalp folliculitis: Case report and literature review.

J Dermatol 2022 Jan 2;49(1):157-160. Epub 2021 Sep 2.

Department of Dermatology, University of Brescia, Brescia, Italy.

Chronic non-scarring scalp folliculitis is a little-known entity included within the spectrum of scalp folliculitis, a group of diseases sharing clinical features but with heterogeneity in terms of residual scarring (always absent in chronic non-scarring scalp folliculitis), microbiology, and response to antibiotics. Chronic non-scarring scalp folliculitis is most likely an inflammatory disease within the group of neutrophilic dermatoses. The recognition of the inflammatory nature of this disease may pave the way for the use of new therapies, directly targeting pathogenic molecules. Herein, we report the first case of chronic non-scarring scalp folliculitis treated by adalimumab.
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http://dx.doi.org/10.1111/1346-8138.16106DOI Listing
January 2022

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis.

Nat Commun 2021 08 11;12(1):4872. Epub 2021 Aug 11.

Istituto di Genetica Molecolare "Luigi Luca Cavalli-Sforza", Consiglio Nazionale delle Ricerche, Pavia, Italy.

The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B's necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.
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http://dx.doi.org/10.1038/s41467-021-24998-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358048PMC
August 2021

Infiltration by CXCL10 Secreting Macrophages Is Associated With Antitumor Immunity and Response to Therapy in Ovarian Cancer Subtypes.

Front Immunol 2021 18;12:690201. Epub 2021 Jun 18.

Unit of Pathology, ASST Spedali Civili di Brescia, Brescia, Italy.

Ovarian carcinomas (OCs) are poorly immunogenic and immune checkpoint inhibitors (ICIs) have offered a modest benefit. In this study, high CD3 T-cells and CD163 tumor-associated macrophages (TAMs) densities identify a subgroup of immune infiltrated high-grade serous carcinomas (HGSCs) with better outcomes and superior response to platinum-based therapies. On the contrary, in most clear cell carcinomas (CCCs) showing poor prognosis and refractory to platinum, a high TAM density is associated with low T cell frequency. Immune infiltrated HGSC are characterized by the 30-genes signature (OC-IS) covering immune activation and IFNγ polarization and predicting good prognosis (n = 312, TCGA). Immune infiltrated HGSC contain CXCL10 producing M1-type TAM (IRF1pSTAT1Y701) in close proximity to T-cells. A fraction of these M1-type TAM also co-expresses TREM2. M1-polarized TAM were barely detectable in T-cell poor CCC, but identifiable across various immunogenic human cancers. Single cell RNA sequencing data confirm the existence of a tumor-infiltrating CXCL10IRF1STAT1 M1-type TAM overexpressing antigen processing and presentation gene programs. Overall, this study highlights the clinical relevance of the CXCL10IRF1STAT1 macrophage subset as biomarker for intratumoral T-cell activation and therefore offers a new tool to select patients more likely to respond to T-cell or macrophage-targeted immunotherapies.
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http://dx.doi.org/10.3389/fimmu.2021.690201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253056PMC
October 2021

E-Cadherin Expression and Blunted Interferon Response in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Am J Surg Pathol 2021 10;45(10):1428-1438

Department of Molecular and Translational Medicine, Section of Pathology.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm derived from plasmacytoid dendritic cells (pDCs). In this study, we investigated by immunohistochemical analysis the expression of E-cadherin (EC) on pDCs in reactive lymph nodes and tonsils, bone marrow, and in BPDCN. We compared the expression of EC in BPDCN to that in leukemia cutis (LC) and cutaneous lupus erythematosus (CLE), the latter typically featuring pDC activation. In BPDCN, we also assessed the immunomodulatory activity of malignant pDCs through the expression of several type I interferon (IFN-I) signaling effectors and downstream targets, PD-L1/CD274, and determined the extent of tumor infiltration by CD8-expressing T cells. In reactive lymph nodes and tonsils, pDCs expressed EC, whereas no reactivity was observed in bone marrow pDCs. BPDCN showed EC expression in the malignant pDCs in the vast majority of cutaneous (31/33 cases, 94%), nodal, and spleen localizations (3/3 cases, 100%), whereas it was more variable in the bone marrow (5/13, 38,5%), where tumor cells expressed EC similarly to the skin counterpart in 4 cases and differently in other 4. Notably, EC was undetectable in LC (n=30) and in juxta-epidermal pDCs in CLE (n=31). Contrary to CLE showing robust expression of IFN-I-induced proteins MX1 and ISG5 in 20/23 cases (87%), and STAT1 phosphorylation, BPDCN biopsies showed inconsistent levels of these proteins in most cases (85%). Expression of IFN-I-induced genes, IFI27, IFIT1, ISG15, RSAD2, and SIGLEC1, was also significantly (P<0.05) lower in BPDCN as compared with CLE. In BPDCN, a significantly blunted IFN-I response correlated with a poor CD8+T-cell infiltration and the lack of PD-L1/CD274 expression by the tumor cells. This study identifies EC as a novel pDC marker of diagnostic relevance in BPDCN. The results propose a scenario whereby malignant pDCs through EC-driven signaling promote the blunting of IFN-I signaling and, thereby, the establishment of a poorly immunogenic tumor microenvironment.
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http://dx.doi.org/10.1097/PAS.0000000000001747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428867PMC
October 2021

TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses.

Nat Commun 2021 04 14;12(1):2237. Epub 2021 Apr 14.

Department of Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy.

Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8 T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8 T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.
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http://dx.doi.org/10.1038/s41467-021-22535-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046802PMC
April 2021

Single-cell analyses of Crohn's disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions.

Nat Commun 2021 03 26;12(1):1921. Epub 2021 Mar 26.

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.

Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated T17 but decreased CD8T, γδT, T and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8, as well as reduced CD4T cells with an elevated T17 over Treg/T ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.
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http://dx.doi.org/10.1038/s41467-021-22164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997960PMC
March 2021

Endogenous Long Pentraxin 3 Exerts a Protective Role in a Murine Model of Pulmonary Fibrosis.

Front Immunol 2021 18;12:617671. Epub 2021 Feb 18.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Pulmonary fibrosis is a progressive scarring disease of the lungs, characterized by inflammation, fibroblast activation, and deposition of extracellular matrix. The long pentraxin 3 (PTX3) is a member of the pentraxin family with non-redundant functions in innate immune responses, tissue repair, and haemostasis. The role played in the lungs by PTX3 during the fibrotic process has not been elucidated. In this study, the impact of PTX3 expression on lung fibrosis was assessed in an intratracheal bleomycin (BLM)-induced murine model of the disease applied to wild type animals, transgenic mice characterized by endothelial overexpression and stromal accumulation of PTX3 (Tie2-PTX3 mice), and genetically deficient animals. Our data demonstrate that PTX3 is produced during BLM-induced fibrosis in wild type mice, and that PTX3 accumulation in the stroma compartment of Tie2-PTX3 mice limits the formation of fibrotic tissue in the lungs, with reduced fibroblast activation and collagen deposition, and a decrease in the recruitment of the immune infiltrate. Conversely, -null mice showed an exacerbated fibrotic response and decreased survival in response to BLM treatment. These results underline the protective role of endogenous PTX3 during lung fibrosis and pave the way for the study of novel PTX3-derived therapeutic approaches to the disease.
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http://dx.doi.org/10.3389/fimmu.2021.617671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930377PMC
June 2021

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

Clin Transl Immunology 2021 16;10(2):e1252. Epub 2021 Feb 16.

Section of Pathology Department of Molecular and Translational Medicine University of Brescia Brescia Italy.

Objectives: The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs.

Methods: The relevance, derivation, phenotype and interactions of nodal TANs were explored a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor-promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial-to-mesenchymal transition (EMT) signatures.

Results: The pan-carcinoma screening identified a consistent infiltration (59%) of CD66b  TANs in tumor-draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra-lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM-CSF. Moreover, by retrospective analysis, a high CD66b TAN density in M-TDLNs of OSCC ( = 182 patients) predicted a worse prognosis. The analysis of the OSCC-TCGA dataset unveiled that the expression of a set of neutrophil-specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66bTANs co-localised with PDPNS100A9 EMT-switched tumor cells in areas of lymphangiogenesis. The pro-EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs.

Conclusion: Our findings are consistent with a novel pro-tumoral TAN compartment that may promote nodal spread EMT, through the lymphatics.
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http://dx.doi.org/10.1002/cti2.1252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886597PMC
February 2021

CT texture analysis for prediction of EGFR mutational status and ALK rearrangement in patients with non-small cell lung cancer.

Radiol Med 2021 Jun 29;126(6):786-794. Epub 2021 Jan 29.

Department of Radiology, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.

Purpose: To develop a CT texture-based model able to predict epidermal growth factor receptor (EGFR)-mutated, anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinomas and distinguish them from wild-type tumors on pre-treatment CT scans.

Materials And Methods: Texture analysis was performed using proprietary software TexRAD (TexRAD Ltd, Cambridge, UK) on pre-treatment contrast-enhanced CT scans of 84 patients with metastatic primary lung adenocarcinoma. Textural features were quantified using the filtration-histogram approach with different spatial scale filters on a single 5-mm-thick central slice considered representative of the whole tumor. In order to deal with class imbalance regarding mutational status percentages in our population, the dataset was optimized using the synthetic minority over-sampling technique (SMOTE) and correlations with textural features were investigated using a generalized boosted regression model (GBM) with a nested cross-validation approach (performance averaged over 1000 resampling episodes).

Results: ALK rearrangements, EGFR mutations and wild-type tumors were observed in 19, 28 and 37 patients, respectively, in the original dataset. The balanced dataset was composed of 171 observations. Among the 29 original texture variables, 17 were employed for model building. Skewness on unfiltered images and on fine texture was the most important features. EGFR-mutated tumors showed the highest skewness while ALK-rearranged tumors had the lowest values with wild-type tumors showing intermediate values. The average accuracy of the model calculated on the independent nested validation set was 81.76% (95% CI 81.45-82.06).

Conclusion: Texture analysis, in particular skewness values, could be promising for noninvasive characterization of lung adenocarcinoma with respect to EGFR and ALK mutations.
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http://dx.doi.org/10.1007/s11547-020-01323-7DOI Listing
June 2021

Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma.

Front Oncol 2020 8;10:600025. Epub 2021 Jan 8.

Section of Hematology and Bone-Marrow Transplant Unit, Department of Medicine, University of Verona, Verona, Italy.

The endothelin-1 (ET-1) receptors were recently found to mediate pro-survival functions in multiple myeloma (MM) cells in response to autocrine ET-1. This study investigated the effectiveness of macitentan, a dual ET-1 receptor antagonist, in MM treatment, and the mechanisms underlying its activities. Macitentan affected significantly MM cell (RPMI-8226, U266, KMS-12-PE) survival and pro-angiogenic cytokine release by down-modulating ET-1-activated MAPK/ERK and HIF-1α pathways, respectively. HIF-1α silencing abrogated the ET-1 mediated induction of genes encoding for pro-angiogenic cytokines such as VEGF-A, IL-8, Adrenomedullin, and ET-1 itself. Upon exposure to macitentan, MM cells cultured in the presence of the hypoxia-mimetic agent CoCl, exogenous ET-1, or CoCl plus ET-1, down-regulated HIF-1α and the transcription and release of downstream pro-angiogenic cytokines. Consistently, macitentan limited significantly the basal pro-angiogenic activity of RPMI-8226 cells in chorioallantoic membrane assay. In xenograft mouse models, established by injecting NOG mice either intra-caudal vein with U266 or subcutaneously with RPMI-8226 cells, macitentan reduced effectively the number of MM cells infiltrating bone marrow, and the size and microvascular density of subcutaneous MM tumors. ET-1 receptors targeting by macitentan represents an effective anti-proliferative and anti-angiogenic therapeutic approach in preclinical settings of MM.
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http://dx.doi.org/10.3389/fonc.2020.600025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820698PMC
January 2021

Pathology of macrophage activation syndrome in humanized NSGS mice.

Res Vet Sci 2021 Jan 16;134:137-146. Epub 2020 Dec 16.

Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.

"Humanized" immunodeficient mice generated via the transplantation of CD34+ human hematopoietic stem cells (hHSC) are an important preclinical model system. The triple transgenic NOD.Cg-PrkdcIl2rg Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ (NSGS) mouse line is increasingly used as recipient for CD34+ hHSC engraftment. NSGS mice combine the features of the highly immunodeficient NSG mice with transgenic expression of the human myeloid stimulatory cytokines GM-CSF, IL-3, and Kit ligand. While generating humanized NSGS (huNSGS) mice from two independent cohorts, we encountered a fatal macrophage activation syndrome (MAS)-like phenotype resulting from the transplantation of CD34+ hHSC. huNSGS mice exhibiting this phenotype declined clinically starting at approximately 10 weeks following CD34+ hHSC engraftment, with all mice requiring euthanasia by 16 weeks. Gross changes comprised small, irregular liver, splenomegaly, cardiomegaly, and generalized pallor. Hematological abnormalities included severe thrombocytopenia and anemia. Pathologically, huNSGS spontaneously developed a disseminated histiocytosis with infiltrates of activated macrophages and hemophagocytosis predominantly affecting the liver, spleen, bone marrow, and pancreas. The infiltrates were chimeric with a mixture of human and mouse macrophages. Immunohistochemistry suggested activation of the inflammasome in both human and murine macrophages. Active Epstein-Barr virus infection was not a feature. Although the affected mice exhibited robust chimerism of the spleen and bone marrow, the phenotype often developed in the face of low chimerism of the peripheral blood. Given the high penetrance and early lethality associated with the MAS-like phenotype here described, we urge caution when considering the use of huNSGS mice for the development of long-term studies.
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http://dx.doi.org/10.1016/j.rvsc.2020.12.003DOI Listing
January 2021

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients.

Crit Rev Oncol Hematol 2020 Dec 3;156:103118. Epub 2020 Oct 3.

Department of Public Health, University of Naples Federico II, Naples, Italy. Electronic address:

In the era of personalized medicine, BRAF mutational assessment is mandatory in advanced-stage melanoma and non-small cell lung cancer (NSCLC) patients. The identification of actionable mutations is crucial for the adequate management of these patients. To date various drugs have been implemented in clinical practice. Similarly, various methods may be adopted for the identification of BRAF mutations. Here, we briefly review the current literature on BRAF in melanoma and NSCLC, focusing attention in particular on the different methods and drugs adopted in these patients. In addition, an overview of the real-world practice in different Italian laboratories with high expertise in molecular predictive pathology testing is provided.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103118DOI Listing
December 2020

The immune receptor CD300e negatively regulates T cell activation by impairing the STAT1-dependent antigen presentation.

Sci Rep 2020 10 5;10(1):16501. Epub 2020 Oct 5.

Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy.

CD300e is a surface receptor, expressed by myeloid cells, involved in the tuning of immune responses. CD300e engagement was reported to provide the cells with survival signals, to trigger the expression of activation markers and the release of pro-inflammatory cytokines. Hence, CD300e is considered an immune activating receptor. In this study, we demonstrate that the ligation of CD300e in monocytes hampers the expression of the human leukocyte antigen (HLA) class II, affecting its synthesis. This effect, which is associated with the transcription impairment of the signal transducer and activator of transcription 1 (STAT1), overcomes the capacity of interferon gamma (IFN-γ) to promote the expression of the antigen-presenting molecules. Importantly, the decreased expression of HLA-II on the surface of CD300e-activated monocytes negatively impacts their capacity to activate T cells in an antigen-specific manner. Notably, unlike in vitro- differentiated macrophages which do not express CD300e, the immune receptor is expressed by tissue macrophages. Taken together, our findings argue against the possibility that this molecule should be considered an activating immune receptor sensu stricto. Moreover, our results support the notion that CD300e might be a new player in the regulation of the expansion of T cell-mediated responses.
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http://dx.doi.org/10.1038/s41598-020-73552-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536427PMC
October 2020

TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy.

Cell 2020 08 11;182(4):886-900.e17. Epub 2020 Aug 11.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2 mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1 and CXCR1 macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.
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http://dx.doi.org/10.1016/j.cell.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485282PMC
August 2020

A Rare Complex BRAF Mutation Involving Codon V600 and K601 in Primary Cutaneous Melanoma: Case Report.

Front Oncol 2020 10;10:1056. Epub 2020 Jul 10.

Unit of Medical Oncology, Spedali Civili di Brescia, Brescia, Italy.

BRAF is one of the most common mutated kinases detected in human cancer, particularly in cases of primary cutaneous melanomas (PCM). Mutations of the BRAF proto-oncogene, at the p.V600 codon, has been detected in more than 50% of primary and metastatic melanoma cells in clinical samples. In addition to the most frequent BRAF p.V600E mutation, corresponding to the single base pair substitution c.1799T>A, rarer mutations, within and outside the V600 codon, have been described. Expectedly, BRAF and MEK inhibitors (or their combination) have been poorly explored as potential therapeutic strategies in metastatic melanomas harboring this rare mutation. By using a set of sequencing techniques and immunohistochemistry, this work reports the genomic and clinical features of two melanoma patients showing a rare complex mutation affecting codon V600 and K601 of the BRAF gene, leading to a V600E2; K601I change. Specifically, these two patients show a distinct clinical behavior and significantly differ in their responses to BRAF and MEK inhibitors. Indeed, although this treatment has proven to be effective and safe in both cases, the observed variability between the two patients resulted as a direct consequence of the baseline extent of brain involvement, intracranial treatment failure as well as on the PTEN status.
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http://dx.doi.org/10.3389/fonc.2020.01056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367153PMC
July 2020

Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis.

Cancers (Basel) 2020 Jul 28;12(8). Epub 2020 Jul 28.

Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAF subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment.
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http://dx.doi.org/10.3390/cancers12082085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463681PMC
July 2020

Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy.

Int J Mol Sci 2020 Jul 23;21(15). Epub 2020 Jul 23.

Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.

Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
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http://dx.doi.org/10.3390/ijms21155207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432207PMC
July 2020

Transient Decrease of Circulating and Tissular Dendritic Cells in Patients With Mycobacterial Disease and With Partial Dominant IFNγR1 Deficiency.

Front Immunol 2020 26;11:1161. Epub 2020 Jun 26.

Department of Clinical and Experimental Sciences, Department of Pediatrics, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia, Italy.

Interferon-γ receptor 1 (IFNγR1) deficiency is one of the inborn errors of IFN-γ immunity underlying Mendelian Susceptibility to Mycobacterial Disease (MSMD). This molecular circuit plays a crucial role in regulating the interaction between dendritic cells (DCs) and T lymphocytes, thus affecting DCs activation, maturation, and priming of T cells involved in the immune response against intracellular pathogens. We studied a girl who developed at the age of 2.5 years a infection characterized by disseminated necrotizing granulomatous lymphadenitis, and we compared her findings with other patients with the same genetic condition. The patient carried a heterozygous 818del4 mutation in the gene responsible of autosomal dominant (AD) partial IFNγR1 deficiency. During the acute infection blood cells immunophenotyping showed a marked reduction in DCs counts, including both myeloid (mDCs) and plasmacytoid (pDCs) subsets, that reversed after successful prolonged antimicrobial therapy. Histology of her abdomen lymph node revealed a profound depletion of tissue pDCs, as compared to other age-matched granulomatous lymphadenitis of mycobacterial origin. Circulating DCs depletion was also observed in another patient with AD partial IFNγR1 deficiency during mycobacterial infection. To conclude, AD partial IFNγR1 deficiency can be associated with a transient decrease in both circulating and tissular DCs during acute mycobacterial infection, suggesting that DCs counts monitoring might constitute a useful marker of treatment response.
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http://dx.doi.org/10.3389/fimmu.2020.01161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333364PMC
April 2021

Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis.

Cancer Res 2020 08 19;80(16):3319-3330. Epub 2020 Jun 19.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

The presence of immunosuppressive macrophages that become activated in the tumor microenvironment constitutes a major factor responsible for tumor growth and malignancy. In line with this knowledge, we report here that macrophage proliferation is a significant feature of advanced stages of cancer. Moreover, we have found that a high proportion of proliferating macrophages in human tumors express ERK5. ERK5 was required for supporting the proliferation of macrophages in tumor grafts in mice. Furthermore, myeloid ERK5 deficiency negatively impacted the proliferation of both resident and infiltrated macrophages in metastatic lung nodules. ERK5 maintained the capacity of macrophages to proliferate by suppressing p21 expression to halt their differentiation program. Collectively, these data provide insight into the mechanism underpinning macrophage proliferation to support malignant tumor development, thereby strengthening the value of ERK5-targeted therapies to restore antitumor immunity through the blockade of protumorigenic macrophage activation. SIGNIFICANCE: These findings offer a new rationale for anti-ERK5 therapy to improve cancer patient outcomes by blocking the proliferative activity of tumor macrophages.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611207PMC
August 2020

Human neutrophils activated by TLR8 agonists, with or without IFNγ, synthesize and release EBI3, but not IL-12, IL-27, IL-35, or IL-39.

J Leukoc Biol 2020 11 1;108(5):1515-1526. Epub 2020 Jun 1.

Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.

The IL-12 family of cytokines plays crucial functions in innate and adaptive immunity. These cytokines include heterodimers sharing distinct α (IL-12A, IL-23A, and IL-27A) with two β (IL-12B and Epstein-Barr virus induced gene 3 [EBI3]) chains, respectively, IL-12 (IL-12B plus IL-12A) and IL-23 (IL-12B plus IL-23A) sharing IL-12B, IL-27 (EBI3 plus IL-27A), IL-35 (EBI3 plus IL-12A), and IL-39 (EBI3 plus IL-23A) sharing EBI3. In this context, we have recently reported that highly pure neutrophils incubated with TLR8 agonists produce functional IL-23. Previously, we showed that neutrophils incubated with LPS plus IFNγ for 20 h produce IL-12. Herein, we investigated whether highly pure, TLR8-activated, neutrophils produce EBI3, and in turn IL-27, IL-35, and IL-39, the IL-12 members containing it. We report that neutrophils incubated with TLR8 ligands, TNFα and, to a lesser extent, LPS, produce and release remarkable amounts of EBI3, but not IL-27A, consequently excluding the possibility for an IL-27 production. We also report a series of unsuccessful experiments performed to investigate whether neutrophil-derived EBI3 associates with IL-23A to form IL-39. Furthermore, we show that neutrophils incubated with IFNγ in combination with either TLR8 or TLR4 ligands express/produce neither IL-12, nor IL-35, due to the inability of IFNγ, contrary to previous findings, to activate IL12A transcription. Even IL-27 was undetectable in supernatants harvested from IFNγ plus R848-treated neutrophils, although they were found to accumulate IL27A transcripts. Finally, by immunohistochemistry experiments, EBI3-positive neutrophils were found in discrete pathologies only, including diverticulitis, cholecystitis, Gorham disease, and Bartonella Henselae infection, implying a specific role of neutrophil-derived EBI3 in vivo.
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http://dx.doi.org/10.1002/JLB.3MA0520-054RDOI Listing
November 2020

Deciphering the fate of slan -monocytes in human tonsils by gene expression profiling.

FASEB J 2020 07 15;34(7):9269-9284. Epub 2020 May 15.

Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.

Monocytic cells perform crucial homeostatic and defensive functions. However, their fate and characterization at the transcriptomic level in human tissues are partially understood, often as a consequence of the lack of specific markers allowing their unequivocal identification. The 6-sulfo LacNAc (slan) antigen identifies a subset of non-classical (NC) monocytes in the bloodstream, namely the slan -monocytes. In recent studies, we and other groups have reported that, in tonsils, slan marks dendritic cell (DC)-like cells, as defined by morphological, phenotypical, and functional criteria. However, subsequent investigations in lymphomas have uncovered a significant heterogeneity of tumor-infiltrating slan -cells, including a macrophage-like state. Based on their emerging role in tissue inflammation and cancer, herein we investigated slan -cell fate in tonsils by using a molecular-based approach. Hence, RNA from tonsil slan -cells, conventional CD1c DCs (cDC2) and CD11b CD14 -macrophages was subjected to gene expression analysis. For comparison, transcriptomes were also obtained from blood cDC2, classical (CL), intermediate (INT), NC, and slan -monocytes. Data demonstrate that the main trajectory of human slan -monocytes infiltrating the tonsil tissue is toward a macrophage-like population, displaying molecular features distinct from those of tonsil CD11b CD14 -macrophages and cDC2. These findings provide a novel view on the terminal differentiation path of slan -monocytes, which is relevant for inflammatory diseases and lymphomas.
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http://dx.doi.org/10.1096/fj.202000181RDOI Listing
July 2020

CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis.

Cancer Immunol Res 2020 06 1;8(6):829-841. Epub 2020 Apr 1.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1aCD207 LCH cells. In LCH, somatic mutations of the gene have been detected in tissue LCH cells, bone marrow CD34 hematopoietic stem cells, circulating CD14 monocytes, and BDCA1 myeloid dendritic cells (DC). Targeting in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAM) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through IHC and flow cytometry that CSF1R is normally expressed on human CD1aCD207 LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14 monocytes, BDCA1 DCs, and CD34 cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including cells) and TAMs retained high expression of CSF1R. We also detected the presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the and wild-type forms of the disease.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0232DOI Listing
June 2020

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma.

Cells 2020 02 11;9(2). Epub 2020 Feb 11.

Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy.

The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells. A distinctive feature of pDCs is the production of high amount of type I Interferon (I-IFN), through the Toll-like receptor (TLR) 7 and 9 signaling pathway activation. However, published data indicate that melanoma-associated escape mechanisms are in place to hijack pDC functions. We have recently reported that pDC recruitment is recurrent in the early phases of melanoma, but the entire pDC compartment collapses over melanoma progression. Here, we summarize recent advances on pDC biology and function within the context of melanoma immunity.
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http://dx.doi.org/10.3390/cells9020417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072514PMC
February 2020

Tumor Infiltrating Neutrophils Are Enriched in Basal-Type Urothelial Bladder Cancer.

Cells 2020 01 25;9(2). Epub 2020 Jan 25.

Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25125 Brescia, Italy.

Background: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy.

Methods: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b tumor-associated-neutrophils (TAN) and CD3 T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed.

Results: Basal type BC contained a significantly higher density of CD66b TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T celsl and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model.

Conclusions: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.
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http://dx.doi.org/10.3390/cells9020291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072276PMC
January 2020
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