Immunomodulation exerted by galectins: a land of opportunity in rare cancers.

Rare cancers represent only 5% of newly diagnosed malignancies. However, in some cases, they account for up to 50% of the deaths attributed to cancer in their corresponding organ. Part of the reason is that treatment options are generally quite limited, non-specific, and very often, only palliative. Needless to say, research for tailored treatments is warranted. Molecules that exert immunomodulation of the tumor microenvironment are attractive drug targets. One such group is galectins. Thus, in this review we summarize the current knowledge about galectin-mediated immunomodulation in rare cancers, highlighting the research opportunities in each case.

Aminopeptidase N/CD13 Crosslinking Promotes the Activation and Membrane Expression of Integrin CD11b/CD18.

The ß2 integrin CD11b/CD18, also known as complement receptor 3 (CR3), and the moonlighting protein aminopeptidase N (CD13), are two myeloid immune receptors with overlapping activities: adhesion, migration, phagocytosis of opsonized particles, and respiratory burst induction. Given their common functions, shared physical location, and the fact that some receptors can activate a selection of integrins, we hypothesized that CD13 could induce CR3 activation through an inside-out signaling mechanism and possibly have an influence on its membrane expression. We revealed that crosslinking CD13 on the surface of human macrophages not only activates CR3 but also influences its membrane expression. Both phenomena are affected by inhibitors of Src, PLCγ, Syk, and actin polymerization. Additionally, after only 10 min at 37 °C, cells with crosslinked CD13 start secreting pro-inflammatory cytokines like interferons type 1 and 2, IL-12p70, and IL-17a. We integrated our data with a bioinformatic analysis to confirm the connection between these receptors and to suggest the signaling cascade linking them. Our findings expand the list of features of CD13 by adding the activation of a different receptor via inside-out signaling. This opens the possibility of studying the joint contribution of CD13 and CR3 in contexts where either receptor has a recognized role, such as the progression of some leukemias.

Cyclic Attractors Are Critical for Macrophage Differentiation, Heterogeneity, and Plasticity.

Adaptability, heterogeneity, and plasticity are the hallmarks of macrophages. How these complex properties emerge from the molecular interactions is an open question. Thus, in this study we propose an actualized regulatory network of cytokines, signaling pathways, and transcription factors to survey the differentiation, heterogeneity, and plasticity of macrophages. The network recovers attractors, which in regulatory networks correspond to cell types, that correspond to M0, M1, M2a, M2b, M2c, M2d, M2-like, and IL-6 producing cells, including multiple cyclic attractors that are stable to perturbations. These cyclic attractors reproduce experimental observations and show that oscillations result from the structure of the network. We also study the effect of the environment in the differentiation and plasticity of macrophages, showing that the observed heterogeneity in macrophage populations is a result of the regulatory network and its interaction with the micro-environment. The macrophage regulatory network gives a mechanistic explanation to the heterogeneity and plasticity of macrophages seen in vivo and in vitro, and offers insights into the mechanism that allows the immune system to react to a complex dynamic environment.

Leukocyte Membrane Enzymes Play the Cell Adhesion Game.

For a long time, proteins with enzymatic activity have not been usually considered to carry out other functions different from catalyzing chemical reactions within or outside the cell. Nevertheless, in the last few years several reports have uncovered the participation of numerous enzymes in other processes, placing them in the category of moonlighting proteins. Some moonlighting enzymes have been shown to participate in complex processes such as cell adhesion. Cell adhesion plays a physiological role in multiple processes: it enables cells to establish close contact with one another, allowing communication; it is a key step during cell migration; it is also involved in tightly binding neighboring cells in tissues, etc. Importantly, cell adhesion is also of great importance in pathophysiological scenarios like migration and metastasis establishment of cancer cells. Cell adhesion is strictly regulated through numerous switches: proteins, glycoproteins and other components of the cell membrane. Recently, several cell membrane enzymes have been reported to participate in distinct steps of the cell adhesion process. Here, we review a variety of examples of membrane bound enzymes participating in adhesion of immune cells.

The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens.

Galectins are a group of evolutionarily conserved proteins with the ability to bind ß-galactosides through characteristic carbohydrate-recognition domains (CRD). Galectin-3 is structurally unique among all galectins as it contains a C-terminal CRD linked to an N-terminal protein-binding domain, being the only chimeric galectin. Galectin-3 participates in many functions, both intra- and extracellularly. Among them, a prominent role for Galectin-3 in inflammation has been recognized. Galectin-3 has also been shown to directly bind to pathogens and to have various effects on the functions of the cells of the innate immune system. Thanks to these two properties, Galectin-3 participates in several ways in the innate immune response against invading pathogens. Galectin-3 has been proposed to function not only as a pattern-recognition receptor (PRR) but also as a danger-associated molecular pattern (DAMP). In this review, we analyze the various roles that have been assigned to Galectin-3, both as a PRR and as a DAMP, in the context of immune responses against pathogenic microorganisms.