Chemokine Heterocomplexes and Cancer: A Novel Chapter to Be Written in Tumor Immunity

Infiltrating immune cells are a key component of the tumor microenvironment and play central roles in dictating tumor fate, either promoting anti-tumor immune responses, or sustaining tumor growth, angiogenesis and metastasis. A distinctive microenvironment is often associated to different tumor types, with substantial differences in prognosis. The production of a variety of chemotactic factors by cancer and stromal cells orchestrates cell recruitment, local immune responses or cancer progression. In the last decades, different studies have highlighted how chemotactic cues, and in particular chemokines, can act as natural antagonists or induce synergistic effects on selective receptors by forming heterocomplexes, thus shaping migratory responses of immune cells. A variety of chemokines has been described to be able to form heterocomplexes both in vitro and in vivo under inflammatory conditions, but nowadays little is known on the presence and relevance of heterocomplexes in the tumor microenvironment. In recent years, the alarmin HMGB1, which can be massively released within the tumor microenvironment, has also been described to form a complex with the chemokine CXCL12 enhancing CXCR4-mediated signaling, thus providing an additional regulation of the activity of the chemokine system. In the present review, we will discuss the current knowledge on the synergy occurring between chemokines or inflammatory molecules, and describe the multiple functions exerted by the chemokines expressed in the tumor microenvironment, pointing our attention to the synergism as a possible modulator of tumor suppression or progression

Modulation of chemokine responses: synergy and cooperativity

Chemokine biology is mediated by more complex interactions than simple monomolecular ligand–receptor interactions, as chemokines can form higher order quaternary structures, which can also be formed after binding to glycosaminoglycans (GAGs) on endothelial cells, and their receptors are found as dimers and/or oligomers at the cell surface. Due to the complexity of the chemokine binding and signaling system, several mechanisms have been proposed to provide an explanation for the synergy observed between chemokines in leukocyte migration. Pioneering studies on interactions between different chemokines have revealed that they can act as antagonists, or synergize with other chemokines. The synergism can occur at different levels, involving either two chemokine receptors triggered simultaneously or sequentially exposed to their agonists, or the activation of one type of chemokine receptor triggered by chemokine heterocomplexes. In addition to the several chemokines that, by forming a heterocomplex with chemokine receptor agonists, act as enhancers of molecules of the same family, we have recently identified HMGB1, an endogenous damage-associated molecular patterns (DAMPs) molecule, as an enhancer of the activity of CXCL12. It is now evident that synergism between chemokines is crucial at the very early stage of inflammation. In addition, the low-affinity interaction with GAGs has recently been shown to induce cooperativity allowing synergy or inhibition of activity by displacement of other ligands

Chemokine heterocomplexes and cancer: A novel chapter to be written in tumor immunity

Infiltrating immune cells are a key component of the tumor microenvironment and play central roles in dictating tumor fate, either promoting anti-tumor immune responses, or sustaining tumor growth, angiogenesis and metastasis. A distinctive microenvironment is often associated to different tumor types, with substantial differences in prognosis. The production of a variety of chemotactic factors by cancer and stromal cells orchestrates cell recruitment, local immune responses or cancer progression. In the last decades, different studies have highlighted how chemotactic cues, and in particular chemokines, can act as natural antagonists or induce synergistic effects on selective receptors by forming heterocomplexes, thus shaping migratory responses of immune cells. A variety of chemokines has been described to be able to form heterocomplexes both in vitro and in vivo under inflammatory conditions, but nowadays little is known on the presence and relevance of heterocomplexes in the tumor microenvironment. In recent years, the alarmin HMGB1, which can be massively released within the tumor microenvironment, has also been described to form a complex with the chemokine CXCL12 enhancing CXCR4-mediated signaling, thus providing an additional regulation of the activity of the chemokine system. In the present review, we will discuss the current knowledge on the synergy occurring between chemokines or inflammatory molecules, and describe the multiple functions exerted by the chemokines expressed in the tumor microenvironment, pointing our attention to the synergism as a possible modulator of tumor suppression or progression

Tracking unlabeled cancer cells imaged with low resolution in wide migration chambers via U-NET class-1 probability (pseudofluorescence).

Cell migration is a pivotal biological process, whose dysregulation is found in many diseases including inflammation and cancer. Advances in microscopy technologies allow now to study cell migration in vitro, within engineered microenvironments that resemble in vivo conditions. However, to capture an entire 3D migration chamber for extended periods of time and with high temporal resolution, images are generally acquired with low resolution, which poses a challenge for data analysis. Indeed, cell detection and tracking are hampered due to the large pixel size (i.e., cell diameter down to 2 pixels), the possible low signal-to-noise ratio, and distortions in the cell shape due to changes in the z-axis position. Although fluorescent staining can be used to facilitate cell detection, it may alter cell behavior and it may suffer from fluorescence loss over time (photobleaching).Here we describe a protocol that employs an established deep learning method (U-NET), to specifically convert transmitted light (TL) signal from unlabeled cells imaged with low resolution to a fluorescent-like signal (class 1 probability). We demonstrate its application to study cancer cell migration, obtaining a significant improvement in tracking accuracy, while not suffering from photobleaching. This is reflected in the possibility of tracking cells for three-fold longer periods of time. To facilitate the application of the protocol we provide WID-U, an open-source plugin for FIJI and Imaris imaging software, the training dataset used in this paper, and the code to train the network for custom experimental settings

Regulation of Dendritic Cell Migration to the Draining Lymph Node: Impact on T Lymphocyte Traffic and Priming

Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7−/− DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor necrosis factor that conditioned the tissue for increased DC migration. These results indicate that DC number and tissue inflammation are critical parameters for DC-based vaccination

Lawan penyakit demi PhD

Kuantan - Semangat yang tinggi untuk menamatkan pengajian di peringkat Doktor Falsafah (PhD) membuatkan pensyarah Bahasa Inggeris Universiti Tenaga Nasional (Uniten) Muadzam Shah, Dr. Umi Kalsom Masrom, 37, tabah melawan penyakit 'adhesion colic' yang dihidapinya dua tahun lalu

Oxidation state dependent conformational changes of HMGB1 regulate the formation of the CXCL12/HMGB1 heterocomplex

High-mobility Group Box 1 (HMGB1) is an abundant protein present in all mammalian cells and involved in several processes. During inflammation or tissue damage, HMGB1 is released in the extracellular space and, depending on its redox state, can form a heterocomplex with CXCL12. The heterocomplex acts exclusively via the chemokine receptor CXCR4 enhancing leukocyte recruitment. Here, we used multi-microsecond molecular dynamics (MD) simulations to elucidate the effect of the disulfide bond on the structure and dynamics of HMGB1. The results of the MD simulations show that the presence or lack of the disulfide bond between Cys23 and Cys45 modulates the conformational space explored by HMGB1, making the reduced protein more suitable to form a complex with CXCL12

From risk charts to guidelines: tools for evaluation and management of cardiovascular risk

Despite the wide improvement of diagnostic techniques and the introduction of effective pharmacological and instrumental therapeutic strategies aimed to the treatment of cardiovascular diseases, their incidence and lethality are still elevated, with economic implications increasingly less sustainable by the public medical systems. The modern practice of cardiovascular prevention requires, thus, that diagnostic and therapeutic interventions, both at population level and on the single patient, should be more and more precise, effective, and appropriate. From this point of view, a correct global cardiovascular risk stratification assumes a preponderant relevance, in order to allow an adequate therapeutical response. For this purpose several work instruments, as risk charts and guidelines, namely dedicated to arterial hypertension and dyslipidemias, were developed and offered to clinicians interested in cardiovascular prevention. The aim of this review is to illustrate, in synthesis, those instruments, aiming to facilitate their implementation, thus reducing the actual gap between theoretical indications and the real world