Sir Peter MacCallum Department of Oncology - Theses

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Start date: 2020 × Subject: Acute myeloid leukaemia × Subject: Cancer epigenetics ×

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    Elucidating epigenetic mechanisms of cancer immune evasion
    Chan, Kah Lok ( 2023-03)
    Cancer immunotherapies have revolutionised the management of a wide range of haematological and solid organ malignancies, due to their potential to induce durable remissions in a proportion of responders. However, primary or acquired resistance remains problematic for the majority of patients, and typically arises from tumour-intrinsic properties that reduce immunogenicity or extrinsic factors promoting an immunosuppressive tumour microenvironment. Effective tumour antigen presentation via major histocompatibility proteins (MHC-I and/or MHC-II) to immune effector cells is a critical component of the adaptive anti-cancer response and genetic disruption of the MHC-I and/or MHC-II antigen presentation pathways, either through inactivating mutations or transcriptional silencing, is a well-recognised cause of resistance to both pharmacological and cellular immunotherapies. In this thesis, I explore epigenetic mechanisms of MHC-I and MHC-II repression in cancer and identify an evolutionarily conserved role for Polycomb repressive complex 2 (PRC2) in MHC-I silencing. I also discover two key mechanisms of MHC-II regulation in acute myeloid leukaemia and melanoma: transcriptional repression of MHC-II pathway genes by the C-terminal binding protein (CtBP) co-repressor complex, and post-translational regulation of CIITA, the master regulator of MHC-II expression, by the FBXO11-containing E3 ubiquitin ligase complex. Targeting of these repressive pathways efficiently upregulates cell surface MHC expression and augments in vitro and in vivo adaptive immune responses. These findings provide valuable biological insights into mechanisms of cancer immune evasion and establish the scientific rationale for further pre-clinical and translational studies of these novel therapeutic strategies to overcome immunotherapy resistance via restoration of tumour antigen presentation.