Mechanisms of retinopathy come into focus

Researchers at the University of Montreal have linked the formation of neutrophil extracellular traps (NETs) to beneficial remodeling of vasculature in retinal diseases. In the developed world, the major causes of blindness lead to deregulated blood vessel growth in the retina. Sometimes such deregulated growth regresses, but the underlying factors for either abnormal growth or its correction have remained blurry. Using both mouse models and patient samples, the researchers showed that retinal damage occurred when epithelial cells entered a senescent state, and could be corrected if neutrophils reacted to the senescence-associated secretory phenotype by forming NETs, which led to clearance of the senescent cells. The authors concluded that “clearance of senescent retinal blood vessels leads to reparative vascular remodeling,” but also cautioned that there was likely an optimal level, and “abundant NETosis in the retina may be incompatible with proper retinal health.” Their work appeared in the Aug. 21, 2020, issue of Science.

New partner in crime for AHR

Researchers at the German Cancer Research Center have identified the enzyme interleukin-4-induced-1 (IL4I1) as an activator of the aryl hydrocarbon receptor (AHR) that promoted tumor progression. The AHR is a transcription factor that promotes tumor progression by suppressing antitumor immunity when it is activated by tryptophan metabolites. The enzymes indoleamine-2,3-dioxygenase 1/2(IDO1/2) or tryptophan-2,3-dioxgenase (TDO2) are the main tryptophan-metabolizing enzymes in humans and activate the AHR. However, clinical inhibition of IDO has not been successful at affecting cancer progression to date. The team hypothesized that this might be due to compensatory activation of AHR by an unknown mechanism. They first developed a tissue-independent way to measure AHR activation, and then looked at correlates of AHR activation across multiple tissue types. They found that across 32 tumor entities, IL4I1 activity associated was more strongly associated with AHR activity than either IDO1 or TDO2, and that its expression was correlated with poor outcomes in mouse models and patient samples. They concluded that “because IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.” They reported their results in the Aug. 19, 2020, online issue of Cell.

Multiple sclerosis’ early days

By looking at the immune signatures of monozygotic twins where one twin had multiple sclerosis (MS) and the other did not, researchers at the University Clinic Muenster have been able to gain new insights into the disease starts. As with many neurological diseases, cell damage in MS starts long before clinical symptoms are apparent. As a result, how MS begins is still unclear. In their work, the authors compared the immune systems of individuals with MS to their apparently healthy siblings. Immune system signatures on the whole were “remarkably” similar, but by focusing on a group of healthy siblings with subtle signs of neuroinflammation but no overt MS, the authors were able to identify differences in memory T cells between sibling pairs. The authors argued that “insight into the immunological mechanisms associated with the initiation of the disease is relevant not only to the therapy but also for prevention of the disease.” They published their paper in the Aug. 17, 2020, online issue of the Proceedings of the National Academy of Sciences.

MMA induces epithelial-to-mesenchymal transition

Researchers at Weill Cornell Medical College have identified methylmalonic acid (MMA) as a mediator of age-related increases in cancer risk. Aging is the largest risk factor overall for cancer in the general population. This is partially due to the cumulative exposure to mutagens, but also due to changes in the extracellular environment such as an increase in proinflammatory mediators secreted by senescent cells. The authors first confirmed that compared to serum from younger people, serum from aged individuals was more likely to induce epithelial-to-mesenchymal transition (EMT)-like changes in cancer cell lines. EMT-promoting changes promote cell motility, which, in tumor cells, makes for increased invasiveness and metastatic propensity. The team then isolated the metabolite MMA as a specific component of blood serum that was responsible for this change. They confirmed their results in vivo. The authors concluded that “metabolic deregulation of the aged host plays a central role in the acquisition of aggressive properties that contribute to tumor progression.” Their work appeared in the Aug. 19, 2020, online issue of Nature.

CAR T cells for inhibition

So far, CAR T cells in clinical practice are used to produce an antitumor immune response. However, regulatory T cells, which inhibit immune responses, are a major component of the adaptive immune response, and could in theory be used in disorders where it is desirable to reduce the immune response. T cells need to be exposed to both an antigen and a co-stimulatory signal from antigen-presenting cells to mount an immune response, and regulatory T cells have different co-stimulatory requirements than killer and helper T cells. Researchers at the University of British Columbia have tested which co-stimulatory domains work best for activating regulatory T cells, and shown that regulatory T cells expressing the costimulatory molecule CD28 were “markedly superior to all other CARs tested in an in vivo model of graft-versus-host disease.” They reported their results in the Aug. 19, 2020, issue of Science Translational Medicine.

Islet organoids can evade immune attack

Scientists at the Salk Institute for Biological Studies have shown that immune-evasive human islet-like organoids ameliorated diabetes in a mouse model of diabetes. Diabetes results from a lack of functioning of a single cell type, insulin-producing pancreatic islet cells, making it, in theory, a great candidate for cell replacement therapy. However, because type I diabetes is an autoimmune disease, a key obstacle has been preventing the destruction of replacement cells by the same autoimmune response that killed the original cells. In their experiments, the authors demonstrated that human islet-like organoids (HILOs) derived from pluripotent stem cells could be programmed to stimulate insulin production in response to glucose. By overexpressing the checkpoint inhibitor PD-1, the organoids were evade immune detection and remain functional for months in immune competent mice. “The generation of glucose-responsive islet-like organoids that are able to avoid immune detection provides a promising alternative to cadaveric and device-dependent therapies in the treatment of diabetes,” the authors concluded. They published their study in the Aug. 19, 2020, issue of Nature.

Cross-reactive immunity helps antitumor response

Investigators at the Gustav Roussy Cancer Center have identified a bacteriophage that set off cross-reactive immunity to cancer neoantigens. The gut microbiome plays a role in the effectiveness of multiple therapies, including antitumor immune therapies such as PD-1/PD-L1 blockade, and understanding that role at a molecular level could bring valuable insights into increasing the response rate to immune oncology treatments. The team investigated a possible role for the bacteriophage Enterococcus hirae, which has been identified previously as possibly playing a role in antitumor immunity. They showed that E. hirae’s tail length tape measure protein (TMP) could be recognized by the host immune system, and that mice who had E. hirae as part of their gut microbiome mounted an antitumor immune response when they were treated with the chemotherapy agent cyclophosphamide, which induces E. hirae to move from the gut to the lymph nodes. Bacteria engineered to express TMP increased the antitumor immune response in mouse models, and a posthoc analysis showed that cancer patients with E. hirae as part of their gut microbiome were more likely to mount a lasting antitumor immune response after checkpoint blockade treatment. The team concluded that “in the microbiota, bacteriophages may enrich the therapeutic armamentarium for modulating the intestinal flora and for stimulating systemic anticancer immune responses.” They published their findings in the Aug. 21, 2020, issue of Science.

How antidepressants inhibit fibrosis

Researchers at the University of California at San Francisco have identified the mechanism by which tricyclic antidepressants (TCAs) can inhibit fibrosis. Fibrosis, the formation of excessive scar tissue after injury, ultimately leads to organ failure. Its origins are poorly understood, but the UCSF team had previously demonstrated that liver fibrosis was driven by hepatic stellate cells, and that TCAs inhibited fibrosis by inhibiting the enzyme acid ceramidase (aCDase), which catalyzes the formation of ceramide. In followup work now published in the Aug. 19, 2020, issue of Science Translational Medicine, the team linked this effect to inhibition of the transcriptional co-activators YAP/TAZ, which had also been shown to reduce fibrosis previously. YAP/TAZ proteasomal degradation could be achieved by inhibiting aCDase. The team also showed that “a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis,” they wrote.

Just add fever

A team at Harvard Medical School has demonstrated that temperature increases, including those mild enough to be clinically viable, killed multiple myeloma cells on their own and synergized with proteasome inhibition. Multiple myeloma is a cancer of the plasma cells, and is exceptionally sensitive to proteasome inhibitors. That sensitivity is likely due to the fact that plasma cells are unusually reliant on the proteasome because they produce large amounts of antibodies and have to degrade those antibodies if they misfold. The authors hypothesized that inducing heat shock, which also increases the degradation of proteins by the proteasome, would be especially problematic for myeloma cells for the same reason. They demonstrated that at temperatures as low as 39C (102.2F), synergized with proteasome inhibition to increase killing of multiple myeloma cells. “Thus, mild hyperthermia, even to only 39 °C, may enhance the efficacy of proteasome inhibitors in the treatment of myeloma,” the authors wrote. They reported their results in the Aug. 17, 2020, online issue of the Proceedings of the National Academy of Sciences.

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