Cancer extracellular vesicles as novel regulators of NK cell response Publication date: Available online 30 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Alessandra Soriani, Elisabetta Vulpis, Lorenzo Cuollo, Angela Santoni, Alessandra Zingoni Abstract Natural killer (NK) cells are innate lymphoid cells that play a major role in the immune surveillance against tumors and their activity is regulated through signals derived by a number of NK cell inhibitory and activating receptors as well as cytokines and other soluble factors released in the tumor microenvironment. Extracellular vesicles (EVs) are membrane-enclosed particles secreted by all cell types, both in healthy and diseased conditions, and are important mediators of intercellular communication. Depending on the molecular cargo, tumor-derived extracellular vesicles have the capability to either promote or suppress NK cell-mediated functions. Anti-cancer therapies designed to sustain host anti-tumor immune response represent an appealing strategy to control tumor growth avoiding tumor immune escape. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Moreover, the activation of the DNA damage response (DDR) and the induction of senescence represent two crucial modalities aimed at promoting the clearance of drug-treated tumor cells by NK cells. Herein, we will address the main mechanisms used by cancer-derived extracellular vesicles to modulate NK cell activity, and we will discuss how anti-cancer therapies might impact on the secretion and the immunomodulatory function of these vesicles. Graphical abstract

LEUKEMIA INHIBITORY FACTOR: RECENT ADVANCES AND IMPLICATIONS IN BIOTECHNOLOGY Publication date: Available online 27 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Vanessa Pinho, Mário Fernandes, André da Costa, Raúl Machado, Andreia C Gomes Abstract Leukemia inhibitory factor (LIF) is a pleiotropic cytokine with several functions in health and disease ranging from inflammation to cancer. LIF is also a potential target and/or therapeutic agent for diseases such as multiple sclerosis, stroke and even psychological disorders, where the function of LIF as a neurotrophic factor has only recently been explored. In recent years, a limited number of LIF clinical trials have been completed, which partially explains the shortage of effective applications as a therapeutic agent. With the increasing interest from biotechnology companies producing recombinant LIF, this status quo will certainly change, and the potential impact of LIF in terms of disease diagnosis, treatment and management will be realized.

Unravelling the insulin-like growth factor I-mediated photoprotection of the skin Publication date: Available online 18 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Melisa J. Andrade, Derek R. Van Lonkhuyzen, Zee Upton, Kapaettu Satyamoorthy Abstract Chronic exposure of human skin to solar ultraviolet radiation (UVR) induces a range of biological reactions which may directly or indirectly lead to the development of skin cancer. In order to overcome these damaging effects of UVR and to reduce photodamage, the skin’s endogenous defence system functions in concert with the various exogenous photoprotectors. Growth factors, particularly insulin-like growth factor-I (IGF-I), produced within the body as a result of cellular interaction in response to UVR demonstrates photoprotective properties in human skin. This review summarises the impact of UVR-induced photolesions on human skin, discusses various endogenous as well as exogenous approaches of photoprotection described to date and explains how IGF-I mediates UVR photoprotective responses at the cellular and mitochondrial level. Further, we describe the current interventions using growth factors and propose how the knowledge of the IGF-I photoprotection signalling cascades may direct the development of improved UVR protection and remedial strategies.

Molecular characteristics and possible functions of innate lymphoid cells in the uterus and gut Publication date: Available online 15 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Lin-Chen Tang, Xiang-Hong Xu, Li-Ping Jin Abstract With the discovery of innate lymphoid cells (ILCs), which are especially enriched in barrier surfaces, the family of innate lymphocytes has grown. A unique characterization of these cells can provide a phenotypical definition of ILCs and their specific functions in different tissue environments. Although ILCs are part of the innate immune system, they are derived from lymphoid lineages lacking rearranged antigen-specific and pattern-recognition receptors. The International Union of Immunological Societies (IUIS) favors the notion that ILCs can be generally divided into five main groups, namely, NK cells, ILC1s, ILC2s, ILC3s and LTi cells. These cells can be specifically stimulated by environmental and pathogen-derived signals. Upon stimulation, ILCs can rapidly secrete a wide range of soluble cytokines that can modulate the functions of effector cells. Over the last decade, ILCs, especially helper ILCs, which do not include NK cells, have been recognized to be a crucial cell type involved in integrating diverse host immune responses. Recently, emerging research has shown that helper ILCs also play a critical role in promoting tissue restoration and immune responses at barrier surfaces. Notably, helper ILCs act as a double-edged sword, being involved in the inflammatory and reparative responses during homeostasis and disease. Therefore, in this review, we summarize the current findings regarding the molecular characteristics and tissue-specific effector functions of helper ILCs in the uterus during physiological and pathological pregnancy and in the intestine during homeostasis and inflammation. Graphical abstract

Senescence in polyploid giant cancer cells: A road that leads to chemoresistance Publication date: Available online 15 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Deblina Bharadwaj, Mahitosh Mandal Abstract Cellular senescence has been associated with age-related diseases, wound healing, fibrosis, diabetes and cancer. Senescent cells lack the capacity to proliferate, but are known to aggravate tumorigenesis. The polyploid giant cells arise from the cancer cell population mainly due to genotoxic stress caused by chemotherapy and/or radiotherapy. They exhibit features of senescence and have been reported to secrete an array of cytokines, chemokines and growth factors. These small molecules can bind to their receptors located on the surface of neighboring cells and activate/deactivate relevant signaling pathways, thereby modulating the tumor microenvironment. Some of these signaling cascade(s) might play a role in imparting therapy resistance to the cancer cells. This review throws light on the incidence of senescence and how the senescent polyploid giant cells affect the tumor microenvironment. Their role in giving rise to chemoresistant cancer cell population as well as acquired chemoresistance in the neighboring cancer cells along with various potential and established therapeutic avenues have also been discussed.

The role of interleukin-18 in pancreatitis and pancreatic cancer Publication date: Available online 9 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Zhiqiang Li, Xiao Yu, Jens Werner, Alexandr V. Bazhin, Jan G. D’Haese Abstract Originally described as an interferon (IFN)-γ-inducing factor, interleukin (IL)-18 has been reported to be involved in Th1 and Th2 immune responses, as well as in activation of NK cells and macrophages. There is convincing evidence that IL-18 plays an important role in various pathologies (i.e. inflammatory diseases, cancer, chronic obstructive pulmonary disease, Crohn's disease and others). Recently, IL-18 has also been shown to execute specific effects in pancreatic diseases, including acute and chronic pancreatitis, as well as pancreatic cancer. The aim of this study was to give a profound review of recent data on the role of IL-18 and its potential as a therapeutic target in pancreatic diseases. The existing data on this topic are in part controversial and will be discussed in detail. Future studies should aim to confirm and clarify the role of IL-18 in pancreatic diseases and unravel their molecular mechanisms. Graphical abstract

The transition model of RTK activation: A quantitative framework for understanding RTK signaling and RTK modulator activity Publication date: Available online 1 November 2019 Source: Cytokine & Growth Factor Reviews Author(s): Michael D. Paul, Kalina Hristova Abstract Here, we discuss the transition model of receptor tyrosine kinase (RTK) activation, which is derived from biophysical investigations of RTK interactions and signaling. The model postulates that (1) RTKs can interact laterally to form dimers even in the absence of ligand, (2) different unliganded RTK dimers have different stabilities, (3) ligand binding stabilizes the RTK dimers, and (4) ligand binding causes structural changes in the RTK dimer. The model is grounded in the principles of physical chemistry and provides a framework to understand RTK activity and to make predictions in quantitative terms. It can guide basic research aimed at uncovering the mechanism of RTK activation and, in the long run, can empower the search for modulators of RTK function.

Cytokines and serum amyloid A in the pathogenesis of hepatitis C virus infection Publication date: Available online 28 October 2019 Source: Cytokine & Growth Factor Reviews Author(s): Sara Abouelasrar Salama, Muriel Lavie, Mieke De Buck, Jo Van Damme, Sofie Struyf Abstract Expression of the acute phase protein serum amyloid A (SAA) is dependent on the release of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α during infection and inflammation. Hepatitis C virus (HCV) upregulates SAA-inducing cytokines. In line with this, a segment of chronically infected individuals display increased circulating levels of SAA. SAA has even been proposed to be a potential biomarker to evaluate treatment efficiency and the course of disease. SAA possesses antiviral activity against HCV via direct interaction with the viral particle, but might also divert infectivity through its function as an apolipoprotein. On the other hand, SAA shares inflammatory and angiogenic activity with chemotactic cytokines by activating the G protein-coupled receptor, formyl peptide receptor 2. These latter properties might promote chronic inflammation and hepatic injury. Indeed, up to 80 % of infected individuals develop chronic disease because they cannot completely clear the infection, due to diversion of the immune response. In this review, we summarize the interconnection between SAA and cytokines in the context of HCV infection and highlight the dual role SAA could play in this disease. Nevertheless, more research is needed to establish whether the balance between those opposing activities can be tilted in favor of the host defense. Graphical abstract

Efficacy and clinical monitoring strategies for immune checkpoint inhibitors and targeted cytokine immunotherapy for locally advanced and metastatic colorectal cancer Publication date: Available online 24 October 2019 Source: Cytokine & Growth Factor Reviews Author(s): Shelby N. Bess, Gage J. Greening, Timothy J. Muldoon Abstract Colorectal cancer (CRC) is the fourth most common cancer type and is the second leading cause of cancer deaths annually in the United States. Conventional treatment options include postoperative (adjuvant) and preoperative (neoadjuvant) chemotherapy and radiotherapy. Although these treatment modalities have shown to decrease tumor burden, a major limitation to chemothearpy/radiotherapy is the high recurrence rate in patients. Immune-modulation strategies have emerged as a promising new therapeutic avenue to reduce this recurrence rate while minimizing undesirable systemic side effects. This review will focus specifically on the mechanisms of monoclonal antibodies: immune checkpoint inhibitors and cytokines, as well as current drugs approved by the Food and Drug Administration (FDA) and new clinical/pre-clinical trials. Finally, this review will investigate emerging methods used to monitor tumor response post-treatment.

Novel activators and small-molecule inhibitors of STAT3 in cancer Publication date: Available online 22 October 2019 Source: Cytokine & Growth Factor Reviews Author(s): Lehe Yang, Shichong Lin, Lingyuan Xu, Jiayuh Lin, Chengguang Zhao, Xiaoying Huang Abstract Excessive activation of signal transducer and activator of transcription 3 (STAT3) signaling is observed in a subset of many cancers, making activated STAT3 a highly promising potential therapeutic target supported by multiple preclinical and clinical studies. However, early-phase clinical trials have produced mixed results with STAT3-targeted cancer therapies, revealing substantial complexity to targeting aberrant STAT3 signaling. This review discusses the diverse mechanisms of oncogenic activation of STAT3, and the small molecule inhibitors of STAT3 in cancer treatment. Graphical abstract