Universitat Rovira i Virgili

An international research team has designed and manufactured a virus-killing surface that could help control disease spread in hospitals, labs and other high-risk environments. An international research team led by RMIT University has designed and manufactured a virus-killing surface that could help control disease spread in hospitals, labs and other high-risk environments. The surface made of silicon is covered in tiny nanospikes that skewer viruses on contact. Lab tests with the hPIV-3 virus -- which causes bronchitis, pneumonia and croup -- showed 96% of the viruses were either ripped apart or damaged to the point where they could no longer replicate to cause infection. These impressive results, featured on the cover of top nanoscience journal ACS Nano, show the material's promise for helping control the transmission of potentially dangerous biological material in laboratories and healthcare environments. Spike the viruses to kill them Corresponding author Dr Natalie Borg, from RMIT's School of Health and Biomedical Sciences, said this seemingly unsophisticated concept of skewering the virus required considerable technical expertise. "Our virus-killing surface looks like a flat black mirror to the naked eye but actually has tiny spikes designed specifically to kill viruses," she said. "This material can be incorporated into commonly touched devices and surfaces to prevent viral spread and reduce the use of disinfectants." The nano spiked surfaces were manufactured at the Melbourne Centre for Nanofabrication, starting with a smooth silicon wafer, which is bombarded with ions to strategically remove material. The result is a surface full of needles that are 2 nanometers thick -- 30,000 times thinner than a human hair -- and 290 nanometers high. Specialists in antimicrobial surfaces The team led by RMIT Distinguished Professor Elena Ivanova has years of experience studying mechanical methods for controlling pathogenic microorganisms inspired by the world of nature: the wings of insects such as dragonflies or cicadas have a nanoscale spiked structure that can pierce bacteria and fungi. In this case, however, viruses are an order of magnitude smaller than bacteria so the needles must be correspondingly smaller if they are to have any effect on them. The process by which viruses lose their infectious ability when they contact the nanostructured surface was analysed in theoretical and practical terms by the research team. Researchers at Spain's Universitat Rovira i Virgili (URV), Dr Vladimir Baulin and Dr Vassil Tzanov, computer simulated the interactions between the viruses and the needles. RMIT researchers carried out a practical experimental analysis, exposing the virus to the nanostructured surface and observing the results at RMIT's Microscopy and Microanalysis Facility. The findings show the spike design to be extremely effective at damaging the virus' external structure and piercing its membranes, incapacitating 96% of viruses that came into contact with the surface within six hours. Study first author, Samson Mah, who completed the work under an RMIT-CSIRO Masters by Research Scholarship and has now progressed to working on his PhD research with the team, said he was inspired by the practical potential of the research. "Implementing this cutting-edge technology in high-risk environments like laboratories or healthcare facilities, where exposure to hazardous biological materials is a concern, could significantly bolster containment measures against infectious diseases," he said. "By doing so, we aim to create safer environments for researchers, healthcare professionals, and patients alike." The project was a truly interdisciplinary and multi-institutional collaboration carried out over two years, involving researchers from RMIT, URV (Spain), CSIRO, Swinburne University, Monash University and the Kaiteki Institute (Japan). This study was supported by the ARC Research Hub for Australian Steel Manufacturing and by the ARC Industrial Transformational Training Centre in Surface Engineering for Advanced Materials.

NEW YORK, March 8, 2024 /PRNewswire/ -- Insights into the workings of an immune cell surface receptor, called PD-1, reveal how treatments that restrict its action can potentially be strengthened to improve their anticancer effect, a new study shows. The same findings also support experimental treatment strategies for autoimmune diseases, in which the immune system attacks the body, because stimulating the action of PD-1, as opposed to restricting it, can potentially block an overactive immune response. Led by researchers at NYU Langone Health's Perlmutter Cancer Center and the University of Oxford, the study is publishing in the journal Science Immunology online March 8. The study results revolve around the body's immune system, which is primed to attack virally infected and cancerous cells while leaving normal cells alone. To spare normal cells from immune attack, the system uses "checkpoints," sensors on the surface of immune cells, including T cells, which turn them off or dampen activation when they receive the right signal. The immune system recognizes tumors as abnormal, but cancer cells can hijack checkpoints to turn off immune responses. Among the most important checkpoints is a protein called programmed cell death receptor 1 (PD-1), which is shut down by a relatively new drug class called checkpoint inhibitors to make tumors "visible" again to immune attack. Such drugs are at least somewhat effective in a third of patients with a variety of cancers, say the study authors, but the field is urgently seeking ways to improve their performance and scope. At the same time, PD-1 signaling is slowed in autoimmune diseases like rheumatoid arthritis, lupus, and type 1 diabetes, such that the action of unchecked immune cells creates inflammation that can damage tissues. Agonists, drugs that stimulate PD-1, are now showing promise in clinical trials. Many immune checkpoints are receptors on the surface of T cells that act to translate docking information from the outside of the cell to the signaling portion of the receptor inside the cell. Connecting the outside-of-the-cell portion of PD-1 with the inside portion is the transmembrane segment. Many immune receptors function in pairs called dimers, but to date, PD-1 has been thought to function alone, not in the dimer form. Study results showed that PD-1 forms a dimer through interactions of its transmembrane segment. Researchers say this finding is in sharp contrast to other immune receptors, which typically form dimers through the segment of the receptor that is outside the cell. Further immune cell testing in mice showed that encouraging PD-1 to form dimers, specifically in the transmembrane domain but not in its outer or inner regions, increased its ability to suppress T cell activity, while decreasing transmembrane dimerization lowered PD-1's ability to inhibit immune cell activity. "Our study reveals that the PD-1 receptor functions optimally as dimers driven by interactions within the transmembrane domain on the surface of T cells, contrary to the dogma that PD-1 is a monomer," said study lead investigator and physician-scientist Elliot Philips, MD, PhD, an internal medicine resident at NYU Grossman School of Medicine and Perlmutter Cancer Center. Philips is also an alumnus of the Vilcek Institute of Biomedical Sciences at NYU. "Our findings offer new insights into the molecular workings of the PD-1 immune cell protein that have proven pivotal to the development of the current generation of anticancer immunotherapies, and which are proving essential in the design and developing of the next generation of immunotherapies for autoimmune diseases," said study co-senior investigator and cancer immunologist Jun Wang, PhD. Wang is an assistant professor in the Department of Pathology at NYU Grossman and Perlmutter. "Our goal is to use our new knowledge of the functioning of PD-1 to determine if weakening its dimerization, or pairing, helps make anticancer immunotherapies more effective, and just as importantly, to see if strengthening its dimerization helps in the design of agonist drugs that quiet overactive T cells, tamping down the inflammation seen in autoimmune diseases," said study co-senior investigator and structural biologist Xiang-Peng Kong, PhD. "Presently, research efforts have focused on strengthening PD-1 interactions with its ligands, or signaling molecules, involved with inhibiting T cell action. "Our new study suggests that efforts to design better drugs should focus on increasing or decreasing PD-1's dimerization to manipulate T cell function," said Kong, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman and Perlmutter. Among the study's other findings was that a single change in the amino acid structure of the transmembrane segment can act to either enhance or diminish the inhibitory function of PD-1 in immune responses. The team plans further investigations of PD-1 inhibitors and agonists to see if they can tailor what they say are more effective, "rationally designed" therapies for both cancer and autoimmune disorders. Funding support for the new study was provided by National Institutes of Health grants R01AI125640, R37CA273333, T32AR069515, and T32GM007308. Additional funding support was provided by NYU Grossman School of Medicine, Kennedy Trust for Rheumatology Research grant 100262Z/12/Z; Research Council of Norway grant 275466, in conjunction with Marie Sklodowska-Curie Actions; Wellcome Trust grant 108869/Z/15/Z; the Melanoma Research Alliance; and a pilot award from the NYU Colton Center for autoimmunity. Wang has been a paid consultant to RootPath Genomics, Bristol Myers Squibb, and Hanmi Pharmaceutical and is a founder, equity holder, and consultant to Remunix. These interests and relationships are being managed in accordance with the policies of NYU Langone Health. Besides Philips, Wang, and Kong, other NYU Langone researchers involved in this study are colead investigator Jia Liu, and coinvestigators Charles Ng, Ian Ahearn, Ruimin Pan, Christina Luo, Alexander Leithner, Zhihua Qin, and Dan Littman, who is also a Howard Hughes Medical Institute investigator. Other study coinvestigators include Audun Kvalvaag, at Oslo University, Norway; Alexander Morch and co-senior investigator Michael Dustin, at the University of Oxford, United Kingdom; Anna Tocheva, at the Icahn School of Medicine at Mount Sinai in New York; Hong Liang and Yong Zhou, at the University of Texas in Houston; Antonio Garcia-Espana, at the University of Rovira i Virgili in Tarragona, Spain; and Adam Mor, at Columbia University in New York. STUDY DOI 10.1126/sciimmunol.ade6256 Media Inquiries: David March 212-404-3528 [email protected] SOURCE NYU Langone Health System

A new study shows how certain cancers neutralize T cells to subvert the immune system and help tumors grow. When cancer arises in the body, it starts with tumor cells that rapidly grow and divide and eventually spread. But what enables these nascent tumor cells to dodge the body's immune system, which is built to identify and fend off an attack from such defective cells? The answer to this question, which long mystified scientists, may be the key to unlocking more effective cancer treatments -- therapies that disable tumors' subversive maneuvers and allow the immune system to do its job. Now, a team led by researchers at Harvard Medical School has identified a way that tumor cells can turn off the immune system, allowing the tumor to grow unchecked. The research, conducted primarily in mice and published Sept. 29 in Science, shows that tumor cells with a particular mutation release a chemical, a metabolite, that weakens nearby immune cells, rendering them less capable of killing cancer cells. The findings reveal critical details of how tumors deactivate the immune system and highlight the role of tumor metabolites in this process. The results also point to the essential role that the area around the tumor -- the tumor microenvironment -- plays in cancer growth. If elucidated through further research, the results could eventually help scientists develop better, more targeted therapies to treat cancers whose growth is fueled by this mechanism. "Our study highlights an immune component in this type of cancer that wasn't fully appreciated before," said senior author Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS. "We now know that a metabolite produced by tumor cells can impact nearby immune cells to make the surrounding environment less hostile for the cancer." Fueling Cancer For the past 15 years, the Haigis lab has been studying the mechanisms that fuel cancer, including tumor metabolites that help cancer cells survive and grow. The research led Haigis and colleagues to the immune system, which works to suppress tumor growth by dispatching immune cells into the tumor microenvironment to kill tumor cells. But how exactly do tumor and immune cells interact? Why do certain tumors survive the immune attack, while others do not? "We became really interested in understanding how metabolites mediate the cross talk between tumor cells and immune cells," Haigis said. The scientists decided to focus their work on tumors with a mutation in a gene called isocitrate dehydrogenase, or IDH. IDH mutations occur in around 3.5 percent of cancers, including solid cancers such as gliomas and blood cancers such as acute myeloid leukemia. In fact, approximately 80 percent of low-grade gliomas and secondary glioblastomas have an IDH mutation. Tumor cells that harbor this mutation secrete D-2-hydroxyglutarate (D-2HG), a metabolite not normally found at high levels in the human body. Previous studies have shown that D-2HG aids the growth of tumor cells by altering their genetic pathways to permanently transform them into a more aggressive, rapidly dividing state. However, very little research has investigated how D-2HG affects other cells in the tumor microenvironment, including CD8+ T cells -- immune cells that release proteins called granzymes and other immune chemicals called cytokines to kill cancer cells. "We had an incomplete picture because much of the focus has been on understanding how this metabolite directly affects cancer cells, whereas its impact on the surrounding cells has been less explored," Haigis explained. In the new study, graduate student and first author Giulia Notarangelo led a series of experiments in mouse models to elucidate how D-2HG interacts with CD8+ T cells in the tumor microenvironment. First, the researchers established that CD8+ T cells sense D-2HG in their environment and take it up. Next, they demonstrated that as soon as CD8+ T cells were exposed to a concentration of D-2HG produced by a tumor, the immune cells immediately slowed down their proliferation and lost their ability to kill tumor cells. Specifically, D-2HG deactivated T cells by inhibiting a key metabolic enzyme called lactate dehydrogenase that plays a role in producing cytokines and granzymes, helping T cells proliferate, and maintaining T cells' tumor-killing capacity. When D-2HG was removed, the T cells regained their ability to kill tumor cells, suggesting that the process is reversible. In another set of experiments, the scientists monitored D-2HG and CD8+ T cells in human glioma tumors with IDH mutations. They found that tumor regions with higher D-2HG levels had lower levels of T-cell infiltration, while tumor regions with more T cells had lower D-2HG levels -- thus supporting the mouse-model findings. "What we found is that this metabolite secreted by the tumor hijacks the body's normal defense mechanism and causes it to break down," Haigis said. She emphasized, however, that "this is only one part of the puzzle, and major questions in the field remain." For example, she hopes future research will delve deeper into D-2HG to identify additional targets and explore how the metabolite affects other cells -- including other immune cells -- in the tumor microenvironment. "The field has initially focused on tumor cell functions of this metabolite, and I think that the door is now open for other studies to look at how it impacts immune cells and the whole microenvironment," Haigis said. Such work, she added, could extend beyond D-2HG to investigate how other metabolites secreted by tumors remodel the tumor microenvironment. Haigis' lab recently published a paper in Cell Metabolism showing that lactate produced by tumor cells similarly reduces the cancer-killing ability of nearby CD8+ T cells. Haigis is also interested in understanding the importance of this D-2HG-T cell mechanism in patients treated with IDH inhibitors -- existing drugs that combat tumor growth by blocking IDH mutations to reduce D-2HG production. "We still don't know the therapeutic implication of this research -- do IDH inhibitors work in part by increasing the activity of the immune system, or do they only act directly on the cancer cells?" Haigis asked. Haigis emphasized that her research focuses on unraveling the basic biology of how tumor cells use metabolites to suppress the immune system. However, she is hopeful that long-term, scientists may be able to use her findings, along with additional research, to develop therapies that take advantage of the interaction between cancer cells and immune cells. Additional authors include Jessica Spinelli, Gregory Baker, Kiran Kurmi, Ilaria Elia, Jia-Ren Lin, Shakchhi Joshi, Jefte Drijvers, Peter Georgiev, Alison Ringel, Elma Zaganjor, and Peter Sorger of HMS; Elizabeth Perez of HMS, the Broad Institute of MIT and Harvard, and Massachusetts General Hospital; Sylwia Stopka and Alexandra Golby of HMS and Brigham and Women's Hospital; Arlene Sharpe and Mario Suvà of HMS and the Broad Institute; Heide Baron of HMS and Mass General; Kai Wucherpfennig of HMS, the Broad Institute, Brigham and Women's, and Dana-Farber Cancer Institute; Sandro Santagata of HMS, the Ludwig Center at Harvard, and Brigham and Women's; Nathalie Agar of HMS, Brigham and Women's, and Dana-Farber; Gerard Baquer, Brigham and Women's and Rovira i Virgili University; and Samuel McBrayer, University of Texas Southwestern Medical Center.