β-Arrestin–biased β-adrenergic signaling promotes extinction learning of cocaine reward memory

1. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. Adel Samson at University of Leeds, St James’s University Hospital in Leeds, UK and his colleagues hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. They show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. They further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, they show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

Read more, please click http://stm.sciencemag.org/content/10/422/eaam7577

2. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy.
Triple-negative breast cancer (TNBC) is an aggressive disease for which treatment options are limited and associated with severe toxicities. Immunotherapeutic approaches like immune checkpoint inhibitors (ICIs) are a potential strategy, but clinical trials have demonstrated limited success in this patient cohort. Clinical studies using ICIs have revealed that patients with preexisting anticancer immunity are the most responsive. Given that oncolytic viruses (OVs) induce antitumor immunity, Marie-Claude Bourgeois-Daigneault at Ottawa Hospital Research Institute in Ottawa, Canada and his colleagues investigated their use as an ICI-sensitizing approach. Using a therapeutic model that mimics the course of treatment for women with newly diagnosed TNBC, they demonstrate that early OV treatment coupled with surgical resection provides long-term benefits. OV therapy sensitizes otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals. They suggest that OV therapy in combination with immune checkpoint blockade warrants testing as a neoadjuvant treatment option in the window of opportunity between TNBC diagnosis and surgical resection.

Read more, please click http://stm.sciencemag.org/content/10/422/eaao1641

3. ATM directs DNA damage responses and proteostasis via genetically separable pathways.
The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. Ji-Hoon Lee at University of Texas at Austin in Austin, USA and his colleagues genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. They found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage–related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of a variant ATM incapable of activation by oxidative stress resulted in widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicate ATM in the control of protein homeostasis.

Read more, please click http://stke.sciencemag.org/content/11/512/eaan5598

4. β-Arrestin–biased β-adrenergic signaling promotes extinction learning of cocaine reward memory.
Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of β-adrenergic receptor (β-AR) during extinction learning is being developed as a potential strategy to treat drug addiction. Bing Huang at Huashan Hospital, Fudan University in Shanghai, China and his colleagues demonstrated that the extinction learning of cocaine-associated memory was mediated by β-arrestin2–biased but not heterotrimeric guanine nucleotide–binding protein (G protein)–dependent β-adrenergic signaling. They found that administration of the nonbiased β-AR antagonist propranolol, but not the G protein–biased β-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex. Overexpression of β-arrestin2 in the infralimbic prefrontal cortex promoted extinction learning, which was blocked by propranolol. Knockout of β-arrestin2 in the infralimbic prefrontal cortex, specifically in excitatory neurons, impaired extinction learning of cocaine-conditioned place preference, which was not rescued by carvedilol. β-Arrestin2 signaling in infralimbic excitatory neurons was also required for the extinction learning in the cocaine self-administration model. Their results suggest that β-arrestin–biased β-adrenergic signaling in the infralimbic prefrontal cortex regulates extinction learning of cocaine-associated memories and could be therapeutically targeted to treat addiction.

Read more, please click http://stke.sciencemag.org/content/11/512/eaam5402

5. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax.
Plasmodium vivax shows a strict host tropism for reticulocytes. Jakub Gruszczyk at The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia and his colleagues identified transferrin receptor 1 (TfR1) as the receptor for P. vivax reticulocyte-binding protein 2b (PvRBP2b). They determined the structure of the N-terminal domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TfR1 recognition. They validated TfR1 as the biological target of PvRBP2b engagement by means of TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of P. vivax but not to invasion of P. falciparum. Using Brazilian and Thai clinical isolates, they show that PvRBP2b monoclonal antibodies that inhibit reticulocyte binding also block P. vivax entry into reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of reticulocytes during P. vivax invasion.

Read more, please click http://science.sciencemag.org/content/359/6371/48

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