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/ß2-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.

Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year-old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3.

Fibroblasts were isolated from a skin biopsy of a clinically diagnosed 51-year-old female attention-deficit/hyperactivity disorder (ADHD) patient carrying a duplication of SLC2A3, a gene encoding neuronal glucose transporter-3 (GLUT3). Patient fibroblasts were infected with Sendai virus, a single-stranded RNA virus, to generate transgene-free human induced pluripotent stem cells (iPSCs). SLC2A3-D2-iPSCs showed expression of pluripotency-associated markers, were able to differentiate into cells of the three germ layers in vitro and had a normal female karyotype. This in vitro cellular model can be used to study the role of risk genes in the pathogenesis of ADHD, in a patient-specific manner.

Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.

Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

Differential modulation of neurite growth by the S- and the L-forms of bag1, a co-chaperone of Hsp70.

Bag1 acts as a cochaperone for Hsp70. However, it also binds to members of the RAF family and to Akt. In addition, bag1 and Hsp70 are part of a complex with glucocorticoid receptors and thus modulate glucocorticoid receptor-mediated transcriptional activation. In the developing nervous system, bag1 is expressed in at least two isoforms. The L-form (bag1L) contains a nuclear localization signal and thus can translocate to the nucleus. In contrast, the S-form (bag1S) is localized exclusively in the cytoplasm. Former studies have shown that B-RAF is essential for neurotrophin-mediated survival signaling in motoneurons and sensory neurons, and that bag1 plays a role in coordinating B-RAF and Akt function in this context. In the absence of B-RAF, embryonic motoneurons and sensory neurons are not able to survive, indicating that bag1 and B-RAF are essential mediators for neuronal survival in response to neurotrophic factors during development. However, the role of the complex containing bag1, Hsp70 and B-RAF in mediating neurite growth in response to neurotrophic factors remained unclear. We have therefore studied the effect of bag1 overexpression in rat phaeochromocytoma (PC12) cells. Upon NGF treatment, proliferating PC12 become postmitotic and grow out neuronal processes. Bag1S overexpression interferes with neurite extension in PC12 cells. In contrast, bag1L does not disturb neurite outgrowth. Interaction of bag1S with Hsp70 appears necessary for this effect. These data indicate that the cytosolic form of bag1 participates in neurotrophin-mediated neurite growth, and that interaction with Hsp70 plays a crucial role in this context.