Nkx2-5+Islet1+ Mesenchymal Precursors Generate Distinct Spleen Stromal Cell Subsets and Participate in Restoring Stromal Network Integrity

SummarySecondary lymphoid organ stromal cells comprise different subsets whose origins remain unknown. Herein, we exploit a genetic lineage-tracing approach to show that splenic fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs), marginal reticular cells (MRCs), and mural cells, but not endothelial cells, originate from embryonic mesenchymal progenitors of the Nkx2-5+Islet1+ lineage. This lineage include embryonic mesenchymal cells with lymphoid tissue organizer (LTo) activity capable also of supporting ectopic lymphoid-like structures and a subset of resident spleen stromal cells that proliferate and regenerate the splenic stromal microenvironment following resolution of a viral infection. These findings identify progenitor cells that generate stromal diversity in spleen development and repair and suggest the existence of multipotent stromal progenitors in the adult spleen with regenerative capacity

Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients

Nd3+-doped phosphate glass waveguides for short length optical amplifier applications

Phosphate glasses have demonstrated in last years to be an alternative host material to silica glass, especially for laser and optical amplification applications. In fact, they can be doped with large amounts of rare earth (RE) ions (up to 1021 ions/cm3) without clustering, therefore enabling the realization of compact active devices with high gain per unit length. Moreover, phosphate glasses possess a large glass forming range, good thermo-mechanical and chemical properties, low nonlinear refractive index and no evidence of photodarkening even at high population inversion. The aim of this research was the realization of different configurations of Nd3+-doped phosphate glass waveguides, in particular a double cladding (DC) optical fibre and circular and D-shaped cladding rods, to be used in lasers and optical amplifiers, in a CW or pulsed regime. Three different phosphate glass compositions (for the core, inner cladding and outer cladding) were designed in order to obtain an adequate numerical aperture between different elements while maintaining similar thermo-mechanical properties in view of the drawing process. The glasses were prepared by conventional melt-quenching technique in a controlled atmosphere furnace at 1400 °C and then cast on pre-heated brass molds. Physical, thermal and spectroscopic properties of the manufactured glasses were measured. The waveguides realized for this research were manufactured by preform drawing with the preforms being obtained by rod-in-tube technique. The fabrication of each preform required one rod of core glass fabricated by melt quenching and one or two tubes shaped by rotational casting, using an in-house built equipment. Fiber drawing was then carried out using a drawing tower developed in-house. The preform and fibre fabrication parameters were set to generate a DC fibre with the following diameters: 8 μm, 35 μm and 105 μm for the core, inner and outer cladding, respectively. Concerning the rods, two distinct sets of samples with different core/cladding dimensions, were manufactured: 310/850 μm and 260/700 μm respectively. Fig 1 shows the cross section of the manufactured waveguides. Laser action at 1.054 μm was demonstrated by cladding pumping 9 cm of the fabricated optical fibre using a semiconductor pigtailed laser diode emitting at 793 nm. With the aim to realize a diode pumped power amplifier for femtosecond sources, preliminary measurements on the manufactured rods were accomplished