Mosaic loss of Chromosome Y in aged human microglia.

Mosaic loss of Chromosome Y (LOY) is a common acquired structural mutation in the leukocytes of aging men that is correlated with several age-related diseases, including Alzheimer's disease (AD). The molecular basis of LOY in brain cells has not been systematically investigated. Here, we present a large-scale analysis of single-cell and single-nuclei RNA brain data sets, yielding 851,674 cells, to investigate the cell type-specific burden of LOY. LOY frequencies differed widely between donors and CNS cell types. Among five well-represented neural cell types, LOY was enriched in microglia and rare in neurons, astrocytes, and oligodendrocytes. In microglia, LOY was significantly enriched in AD subjects. Differential gene expression (DE) analysis in microglia found 172 autosomal genes, three X-linked genes, and 10 pseudoautosomal genes associated with LOY. To our knowledge, we provide the first evidence of LOY in the microglia and highlight its potential roles in aging and the pathogenesis of neurodegenerative disorders such as AD.

Blockade of TGF-ß and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses.

BACKGROUND: Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-ß (TGF-ß) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-ß and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models. METHODS: BA is a first-in-class bifunctional inhibitor of TGF-ß and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models. RESULTS: Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-ß and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls. CONCLUSIONS: Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.