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Archive - Feb 7, 2020

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Mayo Researchers Discover Way to Prime Cancer Tumors for Immunotherapy

A cancer tumor's ability to mutate allows it to escape from chemotherapy and other attempts to kill it. So, encouraging mutations would not seem to be a logical path for cancer researchers. Yet a Mayo Clinic team and their collaborators took that counterintuitive approach and discovered that, while it created resistance to chemotherapy, it also made tumors sensitive to immunotherapy. They also found that this approach worked successfully across tumor types and individual patient genomes. Their findings, involving mouse models and human cells, were published online on February 7, 2020 in Nature Communications. The open-access article is titled “APOBEC3B-Mediated Corruption of the Tumor Cell Immunopeptidome Induces Heteroclitic Neoepitopes for Cancer Immunotherapy.” The international team of researchers based in Rochester, Minnesota and London, and led by Richard Vile (photo), PhD, a Mayo Clinic Professor of Pediatric Oncology, studied models of both pediatric brain tumors and melanoma. They found that, in mice, high levels of the protein APOBEC3B drove a high rate of tumor mutations. Yet, at the same time, these levels of APOBEC3B also sensitized cells to treatment with immune checkpoint blockade, a major mechanism of immunotherapy. "When you put that in the context of vaccine therapy, the mutations generate neoepitopes, a type of peptide that is a prime target for killer T cells," says Dr. Vile. "So that, combined with the checkpoint blockade, make for a potential cross-tumor therapy." The results showed a high rate of cures in subcutaneous melanoma and brain tumor models, and effectiveness no matter the tumor type or location. The results also showed that an individualized approach for each patient is not required.

Breakthrough in Study of Age-Related Macular Degeneration (AMD), the Most Common Cause of Blindness: Complement System-Activating Protein (FHR4) Shown to Be Closely Linked to AMD; Finding May Enable Both Risk Assessment & Treatment

An international team of scientists has identified a protein that is strongly linked to the commonest cause of blindness in developed countries when its levels are raised in the blood. The discovery is a major step forward in the understanding of age-related macular degeneration (AMD), which affects 1.5 million people in the UK alone. The study, carried out by a team from the Universities of Manchester, Cardiff, London, and Nijmegen, and Manchester Foundation NHS Trust was published online on February 7, 2020 in Nature Communications. The open-access article is titled “"Increased Circulating Levels of Factor H Related Protein 4 Are Strongly Associated with Age-Related Macular Degeneration." The protein, Factor H-Related Protein 4 (FHR4), was found by the team to be present at higher levels in the blood of patients with AMD compared to individuals of a similar age without the disease. The findings were confirmed in 484 patient and 522 control samples from two independent collections across Europe. Analyses of eyes donated for research after life also revealed the Factor FHR4 protein was present in the AMD-affected parts of the eye. FHR4 was shown by the team to activate part of the immune system -called the complement system; over-activation of the complement system was already known to be a major causal factor of AMD. FHR4 is one of a group of proteins that regulate the complement system and the genes encoding these proteins are tightly clustered on chromosome 1, the largest human chromosome. When the team investigated a set of genetic variants across the human genome, they found that genetic variants in this region on chromosome 1 determined the levels of FHR4 in the blood. And they found that the same genetic variants were associated with AMD.