The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data.

Primary sclerosing cholangitis (PSC) is an inflammatory and fibrotic biliary disease lacking approved treatment. We studied CCL24, a chemokine shown to be overexpressed in damaged bile ducts, and its involvement in key disease-related mechanisms. Serum proteomics of PSC patients and healthy controls (HC) were analyzed using the Olink proximity extension assay and compared based on disease presence, fibrosis severity, and CCL24 levels.

CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis.

ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease.

Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics.

Given the need to improve the efficacy of standard-of-care immunotherapy (anti-CTLA-4 + anti-PD-1) in human malignant pleural mesothelioma (hMPM), we thoroughly characterized the immunobiology of the AB12 murine mesothelioma (MM) model, aiming to increase its accuracy in predicting the response of hMPM to immunotherapy and in designing novel anti-hMPM treatments. Specifically, we used immunologic, transcriptomic and survival analyses, to synchronize the MM tumor growth phases and immune evolution with the histo-molecular and immunological characteristics of hMPM while also determining the anti-MM efficacy of standard-of-care anti-hMPM immunotherapy as a benchmark that novel therapeutics should meet. We report that early-, intermediate- and advanced- AB12 tumors are characterized by a bell-shaped anti-tumor response that peaks in intermediate tumors and decays in advanced tumors.

Tumor-Associated Neutrophils Drive B-cell Recruitment and Their Differentiation to Plasma Cells.

A major mechanism through which neutrophils have been suggested to modulate tumor progression involves the interaction and subsequent modulation of other infiltrating immune cells. B cells have been found to infiltrate various cancer types and play a role in tumor immunity, offering new immunotherapy opportunities. Nevertheless, the specific impact of tumor-associated neutrophils (TAN) on B cells has largely been overlooked.

Brief ex vivo Fas-ligand incubation attenuates GvHD without compromising stem cell graft performance.

Graft versus host disease (GvHD) remains a limiting factor for successful hematopoietic stem cell transplantation (HSCT). T cells and antigen-presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cell (MPBC) graft. Here we show that a short incubation (2 h) of MPBCs with hexameric Fas ligand (FasL) selectively induces apoptosis of specific donor T cell subsets and APCs but not of CD34 cells.

VICKZ1 enhances tumor progression and metastasis in lung adenocarcinomas in mice.

The VICKZ (Igf2bp) family of RNA binding proteins regulate RNA function at many levels, including intracellular RNA localization, RNA stability, and translational control. One or more of the three VICKZ paralogs are upregulated in many different types of cancers. Here, we show how VICKZ1 enhances, and dominant negative VICKZ1 inhibits, cell migration, growth in soft agar, and wound healing in a mouse lung adenocarcinoma cell line containing a constitutively active, mutant Kras.

Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFα and NO-dependent mechanism, promoting a tumor-supportive environment.

The role of neutrophils in tumor progression has become in recent years a subject of growing interest. Tumor-associated neutrophils (TANs), which constitute an important portion of the tumor microenvironment, promote immunosuppression in advanced tumors by modulating the proliferation, activation and recruitment of a variety of immune cell types. Studies which investigated the consequences of manipulating TAN polarization suggest that the impact of these neutrophils on tumor progression is considerably mediated by and dependent on the presence of CD8 T-cells.

Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs.

It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown.

The diversity of circulating neutrophils in cancer.

Neutrophils, the most abundant leukocyte in human circulation are being more and more recognized as part of the immune reaction to cancer. In the last years, the understanding that neutrophils possess a dual role in cancer development has emerged. During tumor progression the number of neutrophils increase, and their phenotype change.

Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response.

It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models.

Isolation and Characterization of Neutrophils with Anti-Tumor Properties.

Neutrophils, the most abundant of all white blood cells in the human circulation, play an important role in the host defense against invading microorganisms. In addition, neutrophils play a central role in the immune surveillance of tumor cells. They have the ability to recognize tumor cells and induce tumor cell death either through a cell contact-dependent mechanism involving hydrogen peroxide or through antibody-dependent cell-mediated cytotoxicity (ADCC).

Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer.

Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs).

Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17--a new mechanism of impaired antitumor immunity.

The mechanisms by which tumor-associated neutrophils (TANs) affect tumor growth are to a large extent unknown. Regulatory T-cells (T-regs) are functionally immune-suppressive subsets of T-cells. Depletion or inhibition of T-regs can enhance antitumor immunity.

Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression.

The role and characteristics of tumor-associated neutrophils (TAN) in cancer are poorly defined. We have recently shown that TAN can have anti-tumorigenic (N1) or pro-tumorigenic (N2) functions. An interesting unanswered question is how the phenotype of TAN is influenced by the ongoing evolvement of tumor microenvironment.

Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils.

The role of myeloid cells in supporting cancer growth is well established. Most work has focused on myeloid-derived suppressor cells (MDSC) that accumulate in tumor-bearing animals, but tumor-associated neutrophils (TAN) are also known to be capable of augmenting tumor growth. However, little is known about their evolution, phenotype, and relationship to naïve neutrophils (NN) and to the granulocytic fraction of MDSC (G-MDSC).

Recruited macrophages control dissemination of group A Streptococcus from infected soft tissues.

Group A Streptococcus (GAS) causes diverse infections in humans, ranging from mild to life-threatening invasive diseases, such as necrotizing fasciitis (NF), a rapidly progressing deep tissue infection. Despite prompt treatments, NF remains a significant cause of morbidity and mortality, even in previously healthy individuals. The early recruitment of leukocytes is crucial to the outcome of NF; however, although the role of polymorphonuclear neutrophils (PMNs) in host defense against NF is well established, the role of recruited macrophages remains poorly defined.

Functional analysis of the quorum-sensing streptococcal invasion locus (sil).

Group A streptococcus (GAS) causes a wide variety of human diseases, and at the same time, GAS can also circulate without producing symptoms, similar to its close commensal relative, group G streptococcus (GGS). We previously identified, by transposon-tagged mutagenesis, the streptococcal invasion locus (sil). sil is a quorum-sensing regulated locus which is activated by the autoinducer peptide SilCR through the two-component system SilA-SilB.

The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing.

Interleukin-8 (IL-8) promotes neutrophil-mediated host defense through its chemoattractant and immunostimulatory activities. The Group A Streptococcus (GAS) protease SpyCEP (also called ScpC) cleaves IL-8, and SpyCEP expression is strongly upregulated in vivo in the M1T1 GAS strains associated with life-threatening systemic disease including necrotizing fasciitis. Coupling allelic replacement with heterologous gene expression, we show that SpyCEP is necessary and sufficient for IL-8 degradation.

Transcriptional regulation of the sil locus by the SilCR signalling peptide and its implications on group A streptococcus virulence.

In the last two decades an increasing number of local outbreaks of invasive group A streptococcus (GAS) infections including necrotizing fasciitis (NF) have been reported. We identified the streptococcal invasion locus (sil) which is essential for virulence of the M14 strain JS95 isolated from an NF patient. This locus contains six genes: silA/B and silD/E encoding two-component system (TCS) and ABC transporter, respectively, homologous to the corresponding entities in the regulon of Streptococcus pneumoniae involved in genetic competence.

A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues.

Group A Streptococcus (GAS) causes the life-threatening infection in humans known as necrotizing fasciitis (NF). Infected subcutaneous tissues from an NF patient and mice challenged with the same GAS strain possessed high bacterial loads but a striking paucity of infiltrating polymorphonuclear leukocytes (PMNs). Impaired PMN recruitment was attributed to degradation of the chemokine IL-8 by a GAS serine peptidase.