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Villani, Alexandra-Chloe

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Villani

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Alexandra-Chloe

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Villani, Alexandra-Chloe

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2017 - 20193

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Author's Publications: search.filters.isAuthorOfPublication.1cc940eb-77bc-4606-8343-6cdffcd9e4f5

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Now showing 1 - 3 of 3
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    A transcriptomic atlas of aged human microglia
    (Nature Publishing Group UK, 2018) Olah, Marta; Patrick, Ellis; Villani, Alexandra-Chloe; Xu, Jishu; White, Charles C.; Ryan, Katie J.; Piehowski, Paul; Kapasi, Alifiya; Nejad, Parham; Cimpean, Maria; Connor, Sarah; Yung, Christina J.; Frangieh, Michael; McHenry, Allison; Elyaman, Wassim; Petyuk, Vlad; Schneider, Julie A.; Bennett, David A.; De Jager, Philip L.; Bradshaw, Elizabeth M.
    With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype. APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.
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    Targeting the CBM Complex Causes Treg Cells to Prime Tumours for Immune Checkpoint Therapy
    (Springer Science and Business Media LLC, 2019-05-15) Di Pilato, Mauro; Ligorio, Matteo; Kim, Edward; Cadilha, Bruno; Prüßmann, Jasper; Nasrallah, Mazen; Seruggia, Davide; Usmani, Shariq; Misale, Sandra; Zappulli, Valentina; Carrizosa, Esteban; Mani, Vinidhra; Warner, Ross; Medoff, Benjamin; Marangoni, Francesco; Villani, Alexandra-Chloe; Mempel, Thorsten
    Solid tumors are infiltrated by effector T cells (Teff) with the potential to control or reject them, as well as by regulatory T cells (Treg) that restrict the function of Teff and thereby promote tumor growth.1 The anti-tumor activity of Teff can be therapeutically unleashed and is now being exploited for the treatment of some forms of human cancer. However, weak tumor-associated inflammatory responses and the immune-suppressive function of Treg remain major hurdles to broader effectiveness of tumor immunotherapy.2 Here we show that upon disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, the majority of tumor-infiltrating Treg produce IFN-, followed by stunted tumor growth. Remarkably, genetic deletion of both or even just one allele of CARMA1 in only a fraction of Treg, which avoided systemic autoimmunity, was sufficient to produce this anti-tumor effect, showing that not mere loss of suppressive function, but gain of effector activity by Treg initiates tumor control. Treg-production of IFN- was accompanied by macrophage activation and up-regulation of MHC-I on tumor cells. However, tumor cells also up-regulated expression of PD-L1, indicating activation of adaptive immune resistance.3 Consequently, PD-1 blockade concomitant with CARMA1-deletion caused rejection of tumors that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFN--secretion in the preferentially self-reactive Treg pool does not cause systemic autoimmunity but is sufficient to prime the tumor environment for successful immune checkpoint therapy.
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    Publication
    Landscape of X chromosome inactivation across human tissues
    (2017) Tukiainen, Taru; Villani, Alexandra-Chloe; Yen, Angela; Rivas, Manuel A.; Marshall, Jamie; Satija, Rahul; Aguirre, Matt; Gauthier, Laura; Fleharty, Mark; Kirby, Andrew; Cummings, Beryl; Castel, Stephane E.; Karczewski, Konrad; Aguet, François; Byrnes, Andrea; Lappalainen, Tuuli; Regev, Aviv; Ardlie, Kristin G.; Hacohen, Nir; MacArthur, Daniel