ALCAM-mediated cDC1 CD8 T cells interactions are suppressed in advanced lung tumors.

Conventional type 1 dendritic cells (cDC1) are critical regulators of anti-tumoral T-cell responses. The structure and abundance of intercellular contacts between cDC1 and CD8 T cells in cancer tissues is important to determine the outcome of the T-cell response. However, the molecular determinants controlling the stability of cDC1-CD8 interactions during cancer progression remain poorly investigated.

Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis.

Receptors controlling the cross-presentation of tumor antigens by macrophage subsets in cancer tissues are poorly explored. Here, we show that TIM4 large peritoneal macrophages efficiently capture and cross-present tumor-associated antigens at early stages of peritoneal infiltration by ovarian cancer cells. The phosphatidylserine (PS) receptor TIM4 promotes maximal uptake of dead cells or PS-coated artificial targets and triggers inflammatory and metabolic gene programs in combination with cytoskeletal remodeling and upregulation of transcriptional signatures related to antigen processing.

Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors.

Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy).

EMID2 is a novel biotherapeutic for aggressive cancers identified by in vivo screening.

Background: New drugs to tackle the next pathway or mutation fueling cancer are constantly proposed, but 97% of them are doomed to fail in clinical trials, largely because they are identified by cellular or in silico screens that cannot predict their in vivo effect.

Methods: We screened an Adeno-Associated Vector secretome library (> 1000 clones) directly in vivo in a mouse model of cancer and validated the therapeutic effect of the first hit, EMID2, in both orthotopic and genetic models of lung and pancreatic cancer.

Results: EMID2 overexpression inhibited both tumor growth and metastatic dissemination, consistent with prolonged survival of patients with high levels of EMID2 expression in the most aggressive human cancers.

A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by .

Phagosome maturation arrest (PMA) imposed by ( ) is a classic tool that helps evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from -phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA.

CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors.

Lung tumor-infiltrating neutrophils are known to support growth and dissemination of cancer cells and to suppress T cell responses. However, the precise impact of tissue neutrophils on programming and differentiation of anticancer CD8 T cells in vivo remains poorly understood. Here, we identified cancer cell-autonomous secretion of CXCL5 as sufficient to drive infiltration of mature, protumorigenic neutrophils in a mouse model of non-small cell lung cancer (NSCLC).

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to microbial infections, cellular stress, and tissue damage, yet failure to control this mechanism can lead to autoimmune diseases. Several monogenic and multifactorial autoimmune diseases have been associated with type-I interferons and interferon-stimulated genes (ISGs) induced by deregulated recognition of self-DNA.

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons.

Cytoplasmic nucleic acids sensing through cGAS-STING-TBK1 pathway is crucial for the production of antiviral interferons (IFNs). IFN production can also be induced by lipopolysaccharide (LPS) stimulation through Toll-like receptor 4 (TLR4) in appropriate conditions. Of note, both IFN production and dysregulated LPS-response could play a role in the pathogenesis of Systemic Lupus Erythematosus (SLE).

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

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.

Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes.

Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing.

Genetic lineage tracing reveals poor angiogenic potential of cardiac endothelial cells.

Aims: Cardiac ischaemia does not elicit an efficient angiogenic response. Indeed, lack of surgical revascularization upon myocardial infarction results in cardiomyocyte death, scarring, and loss of contractile function. Clinical trials aimed at inducing therapeutic revascularization through the delivery of pro-angiogenic molecules after cardiac ischaemia have invariably failed, suggesting that endothelial cells in the heart cannot mount an efficient angiogenic response.

Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome.

Background: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined.

The SNARE VAMP7 Regulates Exocytic Trafficking of Interleukin-12 in Dendritic Cells.

Interleukin-12 (IL-12), produced by dendritic cells in response to activation, is central to pathogen eradication and tumor rejection. The trafficking pathways controlling spatial distribution and intracellular transport of IL-12 vesicles to the cell surface are still unknown. Here, we show that intracellular IL-12 localizes in late endocytic vesicles marked by the SNARE VAMP7.

A pathobiologic link between risk factors profile and morphological markers of carotid instability.

Objective: Although cardiovascular risk factors have been strongly linked to carotid intimal-media thickness, their association with plaque progression towards instability is poorly understood. We evaluated a large database of endarterectomy specimens removed from symptomatic and asymptomatic patients to determine the correlation between major cardiovascular risk factors and carotid plaque morphology.

Methods: Incidence of thrombotic, vulnerable and stable plaques together with the degree of plaque inflammatory infiltration was evaluated in 457 carotid atherosclerotic lesions.

HLA-A, -B, -C expression in colon carcinoma mimics that of the normal colonic mucosa and is prognostically relevant.

Whether human leukocyte antigen (HLA)-A, -B, -C expression has any predictive value on the prognosis of human malignancies remains controversial. Herein, monoclonal antibodies with preferential reactivity for HLA-A, HLA-B, and HLA-C (HCA2, HC10, and L31) were used to stain an archival collection of 291 formalin-fixed/paraffin-embedded tissues, comprising neoplastic lesions from stages II and III colon carcinoma patients (n=165), and the uninvolved, morphologically normal mucosae from a subset (n=126) of these patients. Marked staining variability was detected not only in the tumors as in previous studies, but also in the normal paired mucosae.

Chromogenic in situ hybridization to detect HER-2/neu gene amplification in histological and ThinPrep-processed breast cancer fine-needle aspirates: a sensitive and practical method in the trastuzumab era.

The increasing evidence of trastuzumab efficacy in breast cancer (BC) patients means that an accurate and reproducible evaluation of HER-2 statusis of paramount importance in histological and in cytological samples. Currently, the two main methods used to analyze HER-2 amplification or overexpression are fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Although the two methods are strongly correlated for histological tissue, the evaluation of tumor morphology through FISH may be difficult and fluorescence fades quickly.

Immunohistochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions.

The p16(INK4a) is a cyclin-dependent kinase inhibitor that decelerates the cell cycle by inactivating the cyclin-dependent kinases involved in the phosphorylation of the retinoblastoma protein (RB). Expression of E6 and E7 oncogenes of high-risk (HR) human papillomavirus (HPV), affecting the RB-p16 pathway, leads to p16 upregulation. Although it is widely reported that p16 is overexpressed in a high percentage of preneoplastic lesions and in almost all carcinomas of the uterine cervix, protein upregulation and its correlation with HPV infection in low-grade lesions is still being debated.

[Anatomico-surgical contribution to the knowledge of the lymphatic spread of gastric adenocarcinoma].

Following the researches performed on lymphatic spread of gastric carcinoma, our study aimed to add useful informations to establish the extension of exeresis with radical intent on the basis of recent studies on sentinel node mapping. The study includes 120 consecutive cases of gastric cancer operated between 1996 and 2000. Sixty-nine (57.