Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these ...therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)—an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.
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•LXR agonism reduces immunosuppressive MDSC levels in mice and cancer patients•LXR transcriptional target ApoE impairs MDSC survival•LXR-induced MDSC depletion enhances activation of cytotoxic T lymphocytes (CTLs)•CTL activation occurs in mice and patients, enhancing tumor immunotherapy in mice
Therapeutic agonism of the LXR/ApoE axis promotes anti-tumor immunity by targeting immunosuppressive innate immune cells.
Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral ...small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.
The effects of two new acetylcholine receptor antagonists, α‐conotoxin MII and α‐conotoxin ImI, on nicotinic synaptic transmission in the 10th paravertebral sympathetic ganglion of the leopard frog ...(Rana pipiens) were examined. The preganglionic nerve was electrically stimulated (at low frequency, 1 min−1, to avoid use‐dependent changes) while compound action potentials of B and C neurones were monitored from the postganglionic nerve.
α‐Conotoxins MII and ImI, at low micromolar concentrations, reversibly blocked both B and C waves. α‐Conotoxin MII blocked the C wave more effectively than the B wave, whereas the potency of α‐conotoxin ImI was opposite that of MII. The observation that nicotinic antagonists can differentially block synaptic transmission of B versus C neurones with opposite selectivities strongly suggests that these neurones possess distinct nicotinic receptors.
In addition to fast and slow B waves described by others, C waves with two temporally distinguishable components were present in our recordings. Each α‐conotoxin affected fast and slow B waves similarly. Likewise, toxins did not discriminate between the two components of C waves. This suggests that all neurones within each major class (B or C) may have the same nicotinic receptors.
Synthetic forms of α‐conotoxins MII and ImI were used in the present study. Their ease of synthesis and their specificities should make these toxins useful probes to investigate the various subtypes of neuronal nicotinic acetylcholine receptors.
British Journal of Pharmacology (1997) 120, 995–1000; doi:10.1038/sj.bjp.0700993
Stem cells reside in specialized niches that regulate their self-renewal and differentiation. The vasculature is emerging as an important component of stem cell niches. However, the role of the ...vasculature in the largest neurogenic niche in the adult mammalian brain, the subventricular zone (SVZ), is unknown. Here, the development, anatomy, and potential function role of the SVZ vasculature is presented. First, studies characterizing the structure and development of the adult SVZ vasculature will be presented. These experiments reveal a uniquely structured vascular plexus composed of a network of planar blood vessels that span the entirety of the SVZ. Next, the relationship between the major known classes of SVZ cell types in the stem cell lineage and the vasculature will be discussed. Adult neural stem cells (NSC) and their transit amplifying progeny are found to be tightly apposed to SVZ blood vessels both during homeostasis and regeneration. Transit amplifying cells frequently contact the vasculature at sites that lack astrocyte endfeet and pericyte coverage, a modification of the blood-brain barrier that is unique to the SVZ. Moreover, regeneration often occurs at these specialized sites. Additionally, circulating tracer molecules injected into the bloodstream are able to access the SVZ. Finally, it will be shown that endothelial cells enhance neural stem cell proliferation via direct contact in vitro. Thus, experiments presented in this thesis demonstrate that the vasculature is a key component of the adult SVZ neural stem cell niche, with SVZ stem cells and transit amplifying cells uniquely poised to receive spatial cues and regulatory signals from diverse elements of the vascular system.
Paramagnetic Mn2+ has emerged in the search for non-invasive magnetic resonance imaging (MRI) techniques to monitor Ca2+ in diagnostic and prognostic cardiovascular disease tests because it both ...alters MRI contrast and behaves as a Ca2+ 'surrogate' in vivo. However, the reliance on macroscopically averaged measurements to infer microscopic processes constitutes a major limitation of MRI. This investigation circumvents this limitation and contributes an MRI-based myocardial Ca2+-transporter assay, which probes the Na+/Ca2+-exchanger involvement in Mn2+ (and presumably Ca2+) transport by virtue of its response to pharmacological inhibition. In the model employed herein, ex vivo arrested rat hearts underwent normoxia and then hypoxia while a constant (hyperkalemic) perfusion minimized flow (and uncontrolled Ca2+-channel) contributions to Mn2+-enhanced MRI measurements. The results (i) demonstrate that Mn2+ (and presumably Ca2+) accumulates via Na+/Ca2+-exchanger-mediated transport during hyperkalemic hypoxia and further, (ii) implicate hypo-perfusion (rather than the diminished participation of an isolated sarcolemmal Ca2+-transporter) as the mechanism that underlies the reported reductions of Mn2+ accumulation (relative to healthy myocardium) subsequent to myocardial insults in MRI studies. Although myriad studies have employed Mn2+-enhanced MRI in myocardial investigations, this appears to be the first attempt to assay the Na+/Ca2+-exchanger with MRI under highly circumscribed conditions. MRI-based Ca2+)transporter assays, such as the Na+/Ca2+-exchanger assay utilized here, will inevitably impact disciplines in the medical sciences and beyond.
Chemical synapses are complex structures that mediate rapid intercellular signalling in the nervous system. Proteomic studies suggest that several hundred proteins will be found at synaptic ...specializations. Here we describe a systematic screen to identify genes required for the function or development of Caenorhabditis elegans neuromuscular junctions. A total of 185 genes were identified in an RNA interference screen for decreased acetylcholine secretion; 132 of these genes had not previously been implicated in synaptic transmission. Functional profiles for these genes were determined by comparing secretion defects observed after RNA interference under a variety of conditions. Hierarchical clustering identified groups of functionally related genes, including those involved in the synaptic vesicle cycle, neuropeptide signalling and responsiveness to phorbol esters. Twenty-four genes encoded proteins that were localized to presynaptic specializations. Loss-of-function mutations in 12 genes caused defects in presynaptic structure.
The complexity and cellular diversity of the adult brain arises from the proliferation and differentiation of a small number of stem cells. The intrinsic state of stem cells depends on their spatial ...and temporal history and affects their responsiveness to extrinsic signals from the microenvironment. Stem cell self-renewal and differentiation along neuronal and glial lineages are defined by the dynamic interplay between transcription, epigenetic control, and posttranscriptional regulators, including microRNAs, whose key role in stem cell biology is just emerging.
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