Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. Experimental cancer immunology and therap

Galactan biosynthesis in snails: a comparative study of beta -(1 6) galactosyltransferases from Helix pomatia and Biomphalaria glabrata

Adult snails synthesize in their albumen glands a polysaccharide which is composed exclusively of D- or D- and L-galactose (Gal) residues which are interglycosidically linked by 1 → 3 and 1 → 6 bonds. It is the only carbohydrate source for embryos and freshly hatched snails. Two galactosyltransferases are described in this study which are most likely involved in the biosynthesis of this polysaccharide. One identified in Helix pomatia acts on oligosaccharides and could be used to synthesize a tetrasaccharide when the branched trisaccharide D-Gal-β-(1 → 3)-[D-Galβ-(1 → 6)]-D-Galβ-1 → OMe was offered as acceptor. This enzyme, requiring Mg++- and Mn++-ions for activity, introduced a linear β-(1 → 6) linkage at the terminal non-reducing ends and was not detected in Biomphalaria glabrata. The other enzyme, which introduced β-(1 → 6) linkages at subterminal D-Gal residues, thus forming branching points in the polysaccharide, was found in H. pomatia, Arianta arbustorum and B. glabrata with comparable activities. With the enzyme preparation of H. pomatia, up to four D-Gal residues were introduced into vicinal positions, forming single-membered side chains, if a hexasaccharide with five linearly β-(1 → 3)-linked D-Gal residues was offered as a acceptor. The multiple-branched structure formed is typical for snail galactans, making this enzyme a prime candidate for the branching enzyme in galactan synthesis. The enzyme activity could be solubilized and purified by affinity chromatography. In SDS-polyacrylamide electrophoresis, the Helix- derived eluate displayed two bands (68, 37 kDa) and that of Biomphalaria five bands (68, 63, 17.5; 15; 13 kDa). The purified material showed only 8% of the total activity of the crude extracts, but it could be shown that a phosphatase present in the crude extract can degrade UDP formed in the transfer reaction and thus drive the reaction to completion

Occurrence of Living Cold-Water Corals at Large Depths Within Submarine Canyons of the Northwestern Mediterranean Sea

14 pagesIn the northwestern Mediterranean Sea, cold-water corals Madrepora oculata, Lophelia pertusa, Dendrophyllia cornigera and Desmophyllum dianthus have been mostly described at relatively shallow depths (i.e. <400 m). Here, we report the results of the inspection of the large, deeply incised Cap de Creus, La Fonera and Blanes submarine canyons in order to assess the presence of cold-water corals at depths between 600 and 1500 m. Two complementary methodologies were applied: remotely operated vehicle dives for in situ observation, and Agassiz trawls to get biological samples. Remotely operated vehicle videos pictured aggregations of specimens of the solitary D. dianthus at 1409 m depth in La Fonera Canyon, which seemed to be alive. This is the first in situ observation of this species at such depths in the northwestern Mediterranean Sea. Agassiz trawl samples provided living M. oculata and L. pertusa in Blanes Canyon at 1200 and 900 m depth, respectively. They also yielded living D. dianthus in Cap de Creus Canyon at 900 m and in Blanes Canyon at 900 and 1200 m depth. Jointly with other recently published results, our findings demonstrate that submarine canyons in the northwestern Mediterranean Sea host significant cold-water coral populations, locally extending to water depths below 1000