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Li, Yvonne Y.

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Li

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Yvonne Y.

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Li, Yvonne Y.

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2016 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.5202b7d7-9378-40c2-9f32-ea925a9e1666

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    Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations
    (Nature Publishing Group, 2017) Li, Yvonne Y.; Chung, Grace T. Y.; Lui, Vivian W. Y.; To, Ka-Fai; Ma, Brigette B. Y.; Chow, Chit; Woo, John K, S.; Yip, Kevin Y.; Seo, Jeongsun; Hui, Edwin P.; Mak, Michael K. F.; Rusan, Maria; Chau, Nicole G.; Or, Yvonne Y. Y.; Law, Marcus H. N.; Law, Peggy P. Y.; Liu, Zoey W. Y.; Ngan, Hoi-Lam; Hau, Pok-Man; Verhoeft, Krista R.; Poon, Peony H. Y.; Yoo, Seong-Keun; Shin, Jong-Yeon; Lee, Sau-Dan; Lun, Samantha W. M.; Jia, Lin; Chan, Anthony W. H.; Chan, Jason Y. K.; Lai, Paul B. S.; Fung, Choi-Yi; Hung, Suet-Ting; Wang, Lin; Chang, Ann Margaret V.; Chiosea, Simion I.; Hedberg, Matthew L.; Tsao, Sai-Wah; van Hasselt, Andrew C.; Chan, Anthony T. C.; Grandis, Jennifer R.; Hammerman, Peter S.; Lo, Kwok-Wai
    Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
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    Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
    (Nature Publishing Group, 2016) Koyama, Shohei; Akbay, Esra A.; Li, Yvonne Y.; Herter-Sprie, Grit S.; Buczkowski, Kevin A.; Richards, William G.; Gandhi, Leena; Redig, Amanda J.; Rodig, Scott J.; Asahina, Hajime; Jones, Robert E.; Kulkarni, Meghana M.; Kuraguchi, Mari; Palakurthi, Sangeetha; Fecci, Peter E.; Johnson, Bruce; Janne, Pasi; Engelman, Jeffrey A; Gangadharan, Sidhu; Costa, Daniel; Freeman, Gordon; Bueno, Raphael; Hodi, F. Stephen; Dranoff, Glenn; Wong, Kwok-Kin; Hammerman, Peter S.
    Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.