Immunomodulatory regulation by heat-labile enterotoxins and potential therapeutic applications.

Introduction: Heat-labile enterotoxins (HLTs) and their cognate ganglioside receptors have been extensively studied because of their therapeutic potential. Gangliosides play arole in modulating effector cells of the immune system, and HLTs provide a novel means for stimulating ganglioside-mediated responses in immunocompetent cells.Areas covered: To evaluate the mechanisms of HLT adjuvanticity, a systemic literature review was performed using relevant keyword searches of the PubMed database, accessing literature published as recently as late 2020. Since HLTs bind to specific ganglioside receptors on immunocytes, they can act as regulators via stimulation or tapering of immune responses from associated signal transduction events. Binding of HLTs to gangliosides can increase proliferation of T-cells, increase cytokine release, augment mucosal/systemic antibody responses, and increase the effectiveness of antigen presenting cells. Subunit components also independently stimulate certain immune responses. Mutant forms of HLTs have potent immunomodulatory effects without the toxicity associated with holotoxins.Expert opinion: HLTs have been the subject of abundant research exploring their use as vaccine adjuvants, in the treatment of autoimmune conditions, in cancer therapy, and for weight loss, proving that these molecules are promising tools in the field of immunotherapy.

Targeting the Platelet-Derived Growth Factor-beta Stimulatory Circuitry to Control Retinoblastoma Seeds.

Purpose: Vitreous seeding remains the primary reason for treatment failure in eyes with retinoblastoma (Rb). Systemic and intra-arterial chemotherapy, each with its own inherent set of complications, have improved salvage rates for eyes with advanced disease, but the location and biology of vitreous seeds present a fundamental challenge in developing treatments with minimal toxicity and risk. The aim of this study was to target the platelet-derived growth factor (PDGF)- PDGF-receptor ß (PDGFRß) signaling pathway and investigate its role in the growth of Rb seeds, apoptotic activity, and invasive potential. Methods: We performed ex vivo analyses on vitreous samples from Rb patients that underwent enucleation and from patient-derived xenografts. These samples were evaluated by quantitative PCR, immunohistochemistry, and ELISA. The effects of disruption of the PDGF-PDGFRß signaling pathway, both by pharmacologic and genomic knockdown approaches, were evaluated in vitro by cell proliferation and apoptotic assays, quantitative PCR analyses, Western blotting, flow cytometry, and imaging flow cytometry. A three-dimensional cell culture system was generated for in-depth study of Rb seeds. Results: Our results demonstrated that PDGFRß signaling is active in the vitreous of Rb patients and patient-derived xenografts, sustaining growth and survival in an AKT-, MDM2-, and NF-κB-dependent manner. The novel three-dimensional cell culture system mimics Rb seeds, as the in vitro generated spheroids have similar morphologic features to Rb seeds and mimicked their natural physiology. Conclusions: Targeting the PDGFRß pathway in vitro reduces Rb cell growth, survival, and invasiveness and could augment current therapies. This represents a novel signaling pathway for potential targeted therapy to further improve ocular survival in advanced Rb.